Cyclic vinylogous amides as bromodomain inhibitors

ABSTRACT

Cyclic vinylogous amides of Formula I are disclosed 
                         
The compounds are useful for treating diseases that arise from inappropriate activity of proteins containing an acetyl-lysine. The compositions comprise a genus of cyclic vinylogous amides that are inhibitors of bromodomain.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/914,672, filed Feb. 26, 2016, now allowed. U.S. patentapplication Ser. No. 14/914,672 is a national phase filing under 35U.S.C. § 371 of PCT International Application PCT/US2014/053527, filedAug. 29, 2014, and published under PCT Article 21(2) in English as WO2015/031824 A1 on Mar. 5, 2015. This application claims priority fromU.S. provisional application 61/872,303, filed Aug. 30, 2013. The entiredisclosures of all of these applications are hereby incorporated hereinby reference.

GOVERNMENT RIGHTS STATEMENT

This invention was made with government support under grant numbersHG004508, CA087658 and DA029963 awarded by National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION Technical Field

The present application relates generally to compositions for treatingdiseases that arise from inappropriate activity of proteins containingan acetyl-lysine. The compositions comprise a genus of cyclic vinylogousamides that are inhibitors of bromodomain.

Background Information

BRD4 is a member of the bromodomains and extra terminal domain (BET)family of proteins that recognize acetylated chromatin structuresthrough their bromodomains and act as transcriptional activators. Brd4functions as an associated factor and positive regulator of P-TEFb, aCdk9-cyclin T heterodimer that stimulates transcriptional elongation byRNA polymerase II. Bromodomain-containing protein 4 (BRD4) contains twotandem bromodomains (BrD1 and BrD2) that bind preferentially toacetylated lysine residues found in histones and nonhistone proteins.This molecular recognition allows Brd4 to associate with acetylatedchromatin throughout the cell cycle and regulates transcription attargeted loci.

Acute myeloid leukemia (AML) is a life-threatening stem cell diseasecharacterized by uncontrolled proliferation and accumulation ofmyeloblasts. In a recent current study, Herrmann et al. [Oncotarget.2012 December; 3(12):1588-99] showed that inhibition of BRD4 by asmall-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosisin primary human AML stem- and progenitor cells, including cells derivedfrom relapsed or refractory patients. In addition, JQ1 was found toinduce apoptosis in CD34+/CD38⁻ and CD34⁺/CD38⁺ stem- and progenitorcells in all donors. BRD4-inhibition is therefore recognized aspromising new therapeutic approach in AML.

NF-κB-mediated inflammation is the major pathology in chronic kidneydiseases, including HIV-associated nephropathy that ultimatelyprogresses to end stage renal disease. HIV infection in the kidneyinduces NF-κB activation, leading to the production of proinflammatorychemokines, cytokines, and adhesion molecules. In a study published inthe Journal of Biological Chemistry, Zhang et al. [J Biol Chem. 2012Nov. 9; 287(46):38956] showed that a Bromodomain and Extra-Terminaldomain-specific bromodomain inhibitor MS417 effectively amelioratedinflammation and kidney injury in HIV-1 transgenic mice, an animal modelfor HIV-associated nephropathy.

Thus, there is a need for inhibitors of BRD4 as therapeutic agents forleukemia and HIV-associated nephropathy.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to compounds of formula I

wherein:

-   U is (CH₂)_(n), where n=1, 2 or 3;-   R¹ is selected from the group consisting of: (C₁-C₁₀)alkyl,    substituted (C₁-C₁₀)alkyl, and nitrile;-   Cy is a carbocycle or heterocycle;-   R¹¹ and R¹² are independently selected from the group consisting of:    H, (C₁-C₁₀)alkyl, (C₁-C₁₀)perfluoroalkyl, halogen, nitrile, hydroxy,    (C₁-C₁₀)alkoxy, perfluoro(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, amino,    (C₁-C₁₀)alkylamino, (C₁-C₁₀)acylamino, aryl, heteroaryl,    aminocarbonyl, carboxyl, and (C₁-C₁₀)alkoxycarbonyl; or

taken together, R¹¹ and R¹² may form a 5, 6, or 7-membered carbocycle orheterocycle wherein said carbocycle or heterocycle may be optionallysubstituted with R²;

-   R² is selected from the group consisting of: halogen, (C₁-C₄)alkyl,    halo(C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,    carboxy, amino, (C₁-C₄)alkylamino and di(C₁-C₄)alkylamino;-   Y is selected from H,

-   L and L′ are independently a bond or (CR³R⁴)_(m) where R³ and R⁴ are    independently selected from the group consisting of H and    (C₁-C₄)alkyl, and m is 1 or 2;-   R¹⁰ is chosen from alkyl, carbocycle and heterocycle, wherein said    alkyl, carbocycle or heterocycle is optionally substituted with R⁷    and/or R⁸;-   R²⁰ is —C(═O)OR²¹;-   R²¹ is chosen from H and (C₁-C₄)alkyl;-   R⁵ and R⁶ are independently selected from the group consisting of    hydrogen, hydroxy, (C₁-C₁₀) hydrocarbyl, halo(C₁-C₁₀)hydrocarbyl,    and (C₁-C₁₀)alkoxy;-   R⁷ and R⁸ are independently selected from the group consisting of:    hydroxy, halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,    hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,    (C₁-C₄)alkylthio, (C₁-C₄)alkylcarbonyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, cyano, oxo, (C₁-C₄)alkylsulfonyl,    amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, (C₁-C₄)acylamino,    aminocarbonyl, carboxyl, and (C₁-C₄)alkoxycarbonyl, where each said    alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, may be    further optionally substituted with hydroxy, oxo, carboxy,    carboxy(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy,    (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl, amino,    (C₁-C₄)alkylamino, di (C₁-C₄)alkylamino, amido, (C₁-C₄)alkylamido,    di (C₁-C₄)alkylamido, halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, aryl,    heteroaryl, heterocycloalkyl, or cycloalkyl;-   or, taken together, R⁵ and R⁶, or R⁷ and R⁸ may form a 5, 6, or    7-membered carbocycle or heterocycle, wherein said carbocycle or    heterocycle is optionally substituted with R⁹;-   R⁹ is selected from the group consisting of: halogen, (C₁-C₄)alkyl,    halo(C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, amino,    (C₁-C₄)alkylamino and di(C₁-C₄)alkylamino.

In a second aspect, the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a compounddescribed herein.

In a third aspect, the invention relates to method for treating adisease or disorder arising from inappropriate activity of proteinscontaining an acetyl-lysine residue. The method comprises administeringto a patient in need thereof a therapeutically effective amount of acompound described herein.

In a fourth aspect, the invention relates to a method for inhibitingbromodomain in a cell. The method comprises contacting the cell with aninhibitory amount of a compound described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of body weight as percent change from baseline vs time(in weeks) for treated and untreated mice in which inflammatory colitishas been induced.

FIG. 2 is a gray-scale rendering of a photograph showing the grossmorphology of the intestines for treated and untreated mice in whichinflammatory colitis has been induced compared to a normal (control)intestine.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention relates to compounds having general formulaI:

In some embodiments, Cy is aliphatic, for example cyclohexyl, orheteroaliphatic; in others it is aryl, for example phenyl or naphthyl,or heteroaryl, for example pyridinyl. When Cy is naphthyl, Y is oftenhydrogen. When Cy is phenyl, the compounds have the general formula:

In some embodiments, U is —CH₂CH₂—, and the vinylogous amide is anN-substituted 3-aminocyclohex-2-enone. In other embodiments, U is —CH₂—,and the vinylogous amide is an N-substituted 3-aminocyclopent-2-enone.In both series, the cycloalkenone is substituted at the 2-position witha substituent R¹. In some embodiments, R¹ is nitrile. In otherembodiments, R¹ is substituted or unsubstituted (C₁-C₁₀)alkyl. In someembodiments, R¹ is preferably (C₁-C₆)alkyl, most commonly methyl.

In some embodiments, R¹¹ and R¹² are independently selected from thegroup consisting of H, (C₁-C₁₀)alkyl, (C₁-C₁₀)perfluoroalkyl, halogen,nitrile, hydroxy, (C₁-C₁₀)alkoxy, perfluoro(C₁-C₁₀)alkoxy,(C₁-C₁₀)alkylthio, amino, (C₁-C₁₀)alkylamino, (C₁-C₁₀)acylamino, aryl,heteroaryl, aminocarbonyl, carboxyl, and (C₁-C₁₀)alkoxycarbonyl. In someembodiments, at least one of R¹¹ and R¹² is hydrogen. In someembodiments, taken together, R¹¹ and R¹² may form a 5, 6, or 7-memberedcarbocycle or heterocycle. In these embodiments, the carbocycle orheterocycle may be optionally substituted with R². In some embodiments,R² is selected from halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, hydroxy,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, carboxy, amino, (C₁-C₄)alkylamino ordi(C₁-C₄)alkylamino.

In some embodiments, Y is a sulfonamide, such as

In some embodiments Y is a urea, such as

In some embodiments Y is a carboxamide, such as

In such compounds, L may be a direct bond, L′ may be a direct bond orboth L and L′ may be direct bonds. In one embodiment, Y is

and both L and L′ are direct bonds, i.e. Y is

In some embodiments, Y is

In these compounds, the wavy line indicates that a particularstereochemical configuration is not designated; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion. In some embodiments, R²⁰ is—C(═O)OR²¹. In some of these embodiments, R²¹ is hydrogen. In some ofthese embodiments, R²¹ is (C₁-C₄)alkyl, particularly methyl. In someembodiments, Y is

In some of these embodiments, R²¹ is (C₁-C₄)alkyl. In other embodiments,R²¹ is hydrogen. In some embodiments, L is a direct bond and R²¹ ishydrogen. In some embodiments, Y is

In these compounds the dotted line represents an optional double bond,which encompasses compounds in which Y is -L-CH₂CH₂—R¹⁰ and-L-CH═CH—R¹⁰. In other embodiments, Y may be a 5-membered heterocycle,particularly an aromatic 5-membered heterocycle, substituted with L-R¹⁰.The 5-membered heterocycle will usually contain more than one heteroatomin the ring, and 1,2,3-triazoles are preferred. When Y is a substituted5-membered heterocycle, L may be —(CR³R⁴)_(m), particularly —CH₂—.

In many embodiments in which Y is a sulfonamide, a urea, a carboxamideor a 5-membered heterocycle, R¹⁰ may be cyclohexyl, cyclopentyl, phenyl,naphthyl, thiophenyl, pyrrolyl, pyridinyl, or pyrimidinyl, eachoptionally substituted with R⁷ and/or R⁸. Cyclohexyl, phenyl andnaphthyl are preferred. When R¹⁰ is phenyl, in some embodiments it maybe only singly substituted with R⁷, and, in those embodiments, thestructure may be represented:

In these compounds, R⁷ may be halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy or aminocarbonyl. Fluoro, chloro,methyl and methoxy are preferred. In some embodiments, R¹⁰ is phenylsubstituted with both R⁷ and R⁸. In these embodiments, R⁷ and R⁸ mayeach independently be halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy or aminocarbonyl. In some embodiments,R⁸ is fluoro.

In a second aspect, the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a compounddescribed herein.

In a third aspect, the invention relates to method for treating adisease or disorder arising from inappropriate activity of proteinscontaining an acetyl-lysine residue. The method comprises administeringto a patient in need thereof a therapeutically effective amount of acompound described herein. In some embodiments, the disease or disorderis chronic inflammation. In some embodiments, the disease or disorder isautoimmune disease. In some embodiments, the disease or disorder iscancer. In some embodiments, an additional therapeutic agent may beadministered.

In a fourth aspect, the invention relates to a method for inhibitingbromodomain in a cell. The method comprises contacting the cell with aninhibitory amount of a compound described herein.

For convenience and clarity certain terms employed in the specification,examples and claims are described herein.

C₁ to C₂₀ hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl,alkenyl, alkynyl, aryl and combinations thereof. Examples includebenzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl andnaphthylethyl. Hydrocarbyl refers to any substituent comprised ofhydrogen and carbon as the only elemental constituents. Aliphatichydrocarbons are hydrocarbons that are not aromatic; they may besaturated or unsaturated, cyclic, linear or branched. Examples ofaliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl,cyclopentyl, norbornyl, etc. Aromatic hydrocarbons include benzene(phenyl), naphthalene (naphthyl), anthracene, etc.

Unless otherwise specified, alkyl (or alkylene) is intended to includelinear or branched saturated hydrocarbon structures and combinationsthereof. Alkyl refers to alkyl groups from 1 to 20 carbon atoms,preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,n-butyl, s-butyl, t-butyl and the like.

Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbongroups of from 3 to 8 carbon atoms. Examples of cycloalkyl groupsinclude cy-propyl, cy-butyl, cy-pentyl, norbornyl and the like.

Unless otherwise specified, the term “carbocycle” is intended to includering systems in which the ring atoms are all carbon but of any oxidationstate. Thus (C₃-C₁₀) carbocycle refers to both non-aromatic and aromaticsystems, including such systems as cyclopropane, benzene andcyclohexene; (C₈-C₁₂) carbopolycycle refers to such systems asnorbornane, decalin, indane and naphthalene. Carbocycle, if nototherwise limited, refers to monocycles, bicycles and polycycles.

Heterocycle means an aliphatic or aromatic carbocycle residue in whichfrom one to four carbons is replaced by a heteroatom selected from thegroup consisting of N, O, and S. The nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. Unless otherwise specified, a heterocycle may benon-aromatic (heteroaliphatic) or aromatic (heteroaryl). Examples ofheterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline,isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan,benzodioxole (commonly referred to as methylenedioxyphenyl, whenoccurring as a substituent), tetrazole, morpholine, thiazole, pyridine,pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole,dioxane, tetrahydrofuran and the like. Examples of heterocyclyl residuesinclude piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically calledthiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl andtetrahydroquinolinyl.

Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms,preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms ofa straight or branched configuration attached to the parent structurethrough an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxyand the like. Lower-alkoxy refers to groups containing one to fourcarbons. For the purpose of this application, alkoxy and lower alkoxyinclude methylenedioxy and ethylenedioxy.

The term “halogen” means fluorine, chlorine, bromine or iodine atoms. Inone embodiment, halogen may be a fluorine or chlorine atom.

Oxaalkyl refers to alkyl residues in which one or more carbons (andtheir associated hydrogens) have been replaced by oxygen. Examplesinclude methoxypropoxy, 3,6,9-trioxadecyl and the like. The termoxaalkyl is intended as it is understood in the art [see Naming andIndexing of Chemical Substances for Chemical Abstracts, published by theAmerican Chemical Society, 2002 edition, ¶196, but without therestriction of 127(a)], i.e. it refers to compounds in which the oxygenis bonded via a single bond to its adjacent atoms (forming ether bonds);it does not refer to doubly bonded oxygen, as would be found in carbonylgroups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues inwhich one or more carbons has been replaced by sulfur or nitrogen,respectively. Examples of azaalkyl include ethylaminoethyl andaminohexyl.

As used herein, the term “optionally substituted” may be usedinterchangeably with “unsubstituted or substituted”. The term“substituted” refers to the replacement of one or more hydrogen atoms ina specified group with a specified radical. For example, substitutedalkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl,cycloalkyl, or heterocyclyl wherein one or more H atoms in each residueare replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxylower alkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy,lower alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl[—C(═O)O-alkyl], alkoxycarbonylamino [HNC(═O)O-alkyl], aminocarbonyl(also known as carboxamido) [—C(═O)NH₂], alkylaminocarbonyl[—C(═O)NH-alkyl], cyano, acetoxy, nitro, amino, alkylamino,dialkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (includingcycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy,heterocyclylalkoxy, mercapto, alkylthio, sulfoxide, sulfone,sulfonylamino, alkylsulfinyl, alkylsulfonyl, acylaminoalkyl,acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl,heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, hydroxyimino,alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino,ureido, benzyloxyphenyl, and benzyloxy. “Oxo” is also included among thesubstituents referred to in “optionally substituted”; it will beappreciated by persons of skill in the art that, because oxo is adivalent radical, there are circumstances in which it will not beappropriate as a substituent (e.g. on phenyl). In one embodiment, 1, 2,or 3 hydrogen atoms are replaced with a specified radical. In the caseof alkyl and cycloalkyl, more than three hydrogen atoms can be replacedby fluorine; indeed, all available hydrogen atoms could be replaced byfluorine. In preferred embodiments, substituents are halogen, haloalkyl,alkyl, acyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, aminocarbonyloxaalkyl, carboxy, cyano, acetoxy, nitro, amino, alkylamino,dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,alkylsulfonylamino arylsulfonyl, arylsulfonylamino, and benzyloxy. Mostpreferred are halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, and aminocarbonyl.

Substituents R^(n) are generally defined when introduced in a claim andretain that definition throughout the all the claims. Certain R^(n) inthe detailed description have definitions that are associated only witha particular set of exemplary syntheses; the Rn in the exemplarysyntheses do not necessarily correlate with the R^(n) in the claims orsummary of the invention.

As used herein, and as would be understood by the person of skill in theart, the recitation of “a compound”—unless expressly further limited—isintended to include salts of that compound. Thus, for example, therecitation “a compound of formula I” as depicted above, whichincorporates a substituent COOH, would include salts in which thesubstituent is COO⁻ M⁺, wherein M is any counterion. Examples 02-01 to02-07 below are examples of such carboxylic acids that can undergo saltformation. Similarly, a compound of formula I as depicted above mayinclude a substituent NH₂, such as in Example 05-25 below, and thereforewould also include salts in which the substituent is NH₃ ⁺X⁻, wherein Xis any counterion. In a particular embodiment, the term “compound offormula I” refers to the compound or a pharmaceutically acceptable saltthereof.

The term “pharmaceutically acceptable salt” refers to salts whosecounter ion derives from pharmaceutically acceptable non-toxic acids andbases. Suitable pharmaceutically acceptable acids for salts of theamino-substituted compounds of the present invention include, forexample, acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic(besylate), benzoic, boric, butyric, camphoric, camphorsulfonic,carbonic, citric, ethanedisulfonic, ethanesulfonic,ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic,glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic,isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic,mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic,pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic,stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic,p-toluenesulfonic, and the like. Suitable pharmaceutically acceptablebase addition salts for the carboxylate-substituted compounds of thepresent invention include, but are not limited to, metallic salts madefrom aluminum, calcium, lithium, magnesium, potassium, sodium and zincor organic salts made from lysine, arginine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium cations and carboxylate, sulfonate and phosphonate anionsattached to alkyl having from 1 to 20 carbon atoms.

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Alternatively, a plurality ofmolecules of a single structure may include at least one atom thatoccurs in an isotopic ratio that is different from the isotopic ratiofound in nature. Radioisotopes of hydrogen, carbon, phosphorous,fluorine, chlorine and iodine include ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ³⁵S,¹⁸F, ³⁶Cl, ¹²⁵I, ¹²⁴I, and ¹³¹I respectively. Compounds that containthose radioisotopes and/or other radioisotopes of other atoms are withinthe scope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e.,¹⁴C, radioisotopes are particularly preferred for their ease inpreparation and detectability. Compounds that contain isotopes ¹¹C, ¹³N,¹⁵O, ¹²⁴I, and ¹⁸F are well suited for positron emission tomography.Radiolabeled compounds of formula I of this invention and prodrugsthereof can generally be prepared by methods well known to those skilledin the art. Conveniently, such radiolabeled compounds can be prepared bycarrying out the procedures disclosed in the Examples and Schemes bysubstituting a readily available radiolabeled reagent for anon-radiolabeled reagent.

Although this invention is susceptible to embodiment in many differentforms, preferred embodiments of the invention are shown. It should beunderstood, however, that the present disclosure is to be considered asan exemplification of the principles of this invention and is notintended to limit the invention to the embodiments illustrated. It maybe found upon examination that certain members of the claimed genus arenot patentable to the inventors in this application. In this event,subsequent exclusions of species from the compass of applicants' claimsare to be considered artifacts of patent prosecution and not reflectiveof the inventors' concept or description of their invention; theinvention encompasses all of the members of the genus I that are notalready in the possession of the public.

While it may be possible for the compounds of formula I to beadministered as the raw chemical, it is preferable to present them as apharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising a compound offormula I or a pharmaceutically acceptable salt or solvate thereof,together with one or more pharmaceutically carriers thereof andoptionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. The compositions may be formulated for oral, topical, orparenteral administration. For example, they may be given intravenously,intraarterially, subcutaneously, and directly into the CNS—eitherintrathecally or intracerebroventricularly.

Formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, andintraarticular), rectal and topical (including dermal, buccal,sublingual, and intraocular) administration. The compounds arepreferably administered orally or by injection (intravenous orsubcutaneous). The precise amount of compound administered to a patientwill be the responsibility of the attendant physician. However, the doseemployed will depend on a number of factors, including the age and sexof the patient, the precise disorder being treated, and its severity.Also, the route of administration may vary depending on the conditionand its severity. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. In general, the formulations are prepared by uniformlyand intimately bringing into association the active ingredient withliquid carriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary, or paste.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining a therapeutic benefit in the form of eradicationor amelioration of the underlying disorder being treated. Also, atherapeutic benefit is achieved with the eradication or amelioration ofone or more of the physiological systems associated with the underlyingdisorder such that an improvement is observed in the patient,notwithstanding that the patient may still be afflicted with theunderlying disorder. The compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological systems of a disease, even though adiagnosis of this disease may not have been made.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes that involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group, whichis used to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes described herein, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference.

A comprehensive list of abbreviations utilized by organic chemistsappears in the first issue of each volume of the Journal of OrganicChemistry. The list, which is typically presented in a table entitled“Standard List of Abbreviations”, is incorporated herein by reference.

In general, the compounds of the present invention may be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants that are inthemselves known, but are not mentioned here. The starting materials areeither commercially available, synthesized as described in the examplesor may be obtained by the methods well known to persons of skill in theart. Standard synthetic methods and procedures for the preparation oforganic molecules and functional group transformations and manipulationscan be readily obtained from the relevant scientific literature or fromstandard textbooks in the field. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given;other process conditions can also be used unless otherwise stated.Optimum reaction conditions can vary with the particular reactants orsolvent used. Those skilled in the art will recognize that the natureand order of the synthetic steps presented can be varied for the purposeof optimizing the formation of the compounds described.

The reactions or the processes described herein can be carried out insuitable solvents, which can be readily selected by one skilled in theart. Suitable solvents typically are substantially nonreactive with thereactants, intermediates, and/or products at the temperatures at whichthe reactions are carried out, i.e., temperatures that can range fromthe solvent's freezing temperature to the solvent's boiling temperature.A given reaction can be carried out in one solvent or a mixture of morethan one solvent. Depending on the particular reaction step, suitablesolvents for a particular reaction step can be selected.

The description of this invention utilizes conventional AmericanChemical Society abbreviations well known to those skilled in the art,in addition to the following:

AcCl: acetyl chloride

Ac₂O: acetic anhydride

AcOH: acetic acid

Alk: alkyl

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

cat: catalytic

CH₂Cl₂: dichloromethane; methylenechloride

CHCl₃: chloroform

Δ: heat

DI H₂O: deionized water

DMA: dimethylacetamide

DMF-DMA: 1,1-dimethyoxy-N,N-dimethylmethanamine

DMF: N,N-dimethylformamide

EDCCl: 3-(ethyliminomethylene-amino)-N,N-dimethyl-propan-1-aminehydrochloride

eq: equivalence

ESS: eluting solvent system

EtOAc: ethyl acetate

EtOH: ethanol

H⁺: acid

HCl: hydrochloric acid

HCO₂H: formic acid

IBCF: isobutylchloroformate

LCMS: liquid chromatography mass spectra

MeOH: methanol

NaOH: sodium hydroxide

NMM: N-methylmorpholine

PG: protecting group

PS-CDI: polystyrene carbodiimidazole

pTSA: para-toluensulfonic acid

rt: room temperature

sat: saturated

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TMS: tetramethylsilane

¹H Nuclear Magnetic Resonance (NMR) spectra were in all cases consistentwith the proposed structures. ¹³CNMR spectra were in relevant casesconsistent with the proposed structures. NMR were acquired on a Bruker®DRX-600 spectrometer at 600 MHz for ¹H and 125 MHz for ¹³C.Characteristic chemical shifts (6) are expressed in parts per milliondownfield from tetramethylsilane (TMS) using conventional abbreviationsfor designation of major peaks: s, singlet; d, doublet; t, triplet; q,quartet; m, multiplet; br, broad. The following abbreviations have beenused for common solvents: CDCl₃, deuterochloroform; D6-DMSO,deuterodimethyl-sulfoxide; MeOD, deuteromethanol.

Mass Spectra were in all cases consistent with the proposed structures.Liquid chromatography mass spectra, LCMS, with retention time, t, inminutes, min, and with mass to charge ratio, m/z, were recorded usingpeak elution time and electrospray ionization, ESI. LCMS analysis wasperformed on an Agilent® 1200 HPLC equipped with a Zorbax® 300SB-C18column held at 45° C., and a G1969A API-TOF in positive mode. Purity ofall Examples was estimated at >95% by the DAD trace using the followingLC method: solvent system (A)/(B) with 0.1% buffer=H₂O/acetonitrile withformic acid, flow rate=0.4 mL/min, and timed percentage of solvent B=0-1min (1%), gradient 1-4 min (1-99%), 4-8 min (99%). Theoretical mass tocharge ratios were calculated, Calcd, using ChemDraw® software. Inrelevant cases identifiable, radical cation of mass plus hydrogen,[M+H]⁺; mass plus sodium, [M+Na]⁺; two masses plus hydrogen, [2M+H]⁺;and two masses plus sodium, [2M+Na]⁺ data were recorded. In relevantExamples containing bromine atoms, the two stable isotopes ⁷⁹Br and⁸¹Br, for [M+H]⁺ and [M+Na]⁺ were recorded.

Melting points (mp) were determined on an automated Standford ResearchSystem OptiMelt MPA100 heating at a rate of 10° C./min.

Synthetic Procedures

In the tabulated experimental details that follow, the Examples andIntermediates were prepared according to the corresponding referencemethod (i.e. Example 01-01, Intermediate 03, and so on). The skilledperson will appreciate that, in the synthesis of any specific Example orIntermediate, it may be necessary to make minor variations to thereaction conditions and purification procedures of the reference method(e.g. with regard to ratios, time, and so on).

Reagents used in the preparation of the compounds of this invention canbe either obtained commercially or prepared by standard literatureprocedures. Unless otherwise stated, all reagents and solvents wereobtained from commercial suppliers and used without furtherpurification.

Certain compounds of the Examples and Preparations were continuouslyirradiated at 2.45 gigahertz, GHz in a sealed microwave vial containedin a single mode Biotage®-Initiator cavity.

Certain compounds of the Examples and Preparations were purified usingautomated chromatography. Isocratic, or stepwise gradient mobile phaseswere used on normal-phase KP-Sil™ silica-gel columns attached to aBiotage®-Isolera Four instrument, monitoring UV Trace at 254 nm and 365nm. Solvent systems utilized one, two, or three solvents (acetone,hexanes, EtOAc, or MeOH) running from non-polar to polar steps. ElutingSolvent System (ESS) is the solvent step which eluted the product and isindicated below in the following format ESS=H:E (X:X), or the percentageof MeOH (%) in EtOAc. Additional monitoring by analytical thin layerchromatography (TLC) was performed employing EMD Chemicals Inc. TLCSilica gel 60 F254 on aluminium, visualized either by exposure to UVlight or, staining agents such as: iodine impregnated silica gel; 10%phosphomolybdic acid in EtOH and so on.

Schemes 1-4 present general synthetic approaches. The details of eachexample are described in the Examples. Compounds may be preparedaccording to the reactions in Scheme 1. R¹ can be present fromcommercial reagents, added through C-alkylation, or formed through ringopening chemistry. R² can be hydrogen, present from commercial reagents,or prepared as in Scheme 2, have appended acid, ester, nitro, orprotected amine functionalities. R⁸ can be from reagents bearing ahalogen.

Appended acid, or ester, compounds can undergo reactions in Scheme 2.Compounds can be protected commercial reagents, or from Scheme 1. R³ canbe added with an appended ester functionality and undergo a seconditeration of base hydrolysis and amide bond formation.

Amine compounds, deprotected or reduced from nitro, can undergoreactions in Scheme 3. R⁵ can be from carboxylic acids, acid halides,anhydrides, cyclic anhydrides, or activated acids. R⁶ can be fromsulfonic acids, or sulfonyl chlorides. R⁷ can be from aldehydes. R⁸ canbe from reagents bearing a halogen.

Alkynes can undergo reactions in Scheme 4. R⁹ can be from azides oramines.

Specific Examples follow:

Intermediate 01 Preparation of 2-Benzylcyclopentane-1,3-dione(Intermediate 01)

1,3-Cyclopentandione (0.98 g, 10.0 mmol, 1.0 eq, Synth. Comm. 1993,23(22), p. 3095-3108) was treated with 40% aq Triton B (3.95 mL<1.0 eq)in DI H₂O (5.0 mL) followed by benzyl bromide (1.4 mL, 1.2 eq). Thereaction mixture was stirred at rt for 24 h. The crude was extractedwith EtOAc and dried over anhyd sodium sulfate. The reaction on a 10.0mmol scale yielded 0.9 g of the title intermediate afterrecrystallization from EtOAc (48% yield). ¹H NMR (D6-DMSO) δ 2.39 (br s,4H), 3.36 (br s, 2H), 7.10-7.17 (m, 3H), 7.20-7.25 (m, 2H), 11.71 (br s,1H). LCMS t=4.3 min, m/z Calcd for C₁₂H₁₃O₂; C₁₂H₁₂NaO₂; C₂₄H₂₅O₄;C₂₄H₂₄NaO₄ 189.09; 211.07; 377.16; 399.16 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 189.18; 211.14; 377.16; 399.13.

Intermediate 02 Preparation of 2-(4-Hydroxybenzyl)cyclopentane-1,3-dione(Intermediate 02)

1,3-Cyclopentandione (491 mg, 5.0 mmol, 1.0 eq, J. Org. Chem. 1988, 53,p. 891-893) was treated with AcOH (315 mL, 1.1 eq) followed byp-hydroxybenzyl alcohol (683 mg, 1.1 eq). Microwave irradiation wasapplied to a sealed microwave vial for 10 min in a single modeBiotage®-Initiator cavity, producing continuous irradiation to hold 120°C. at 2.45 GHz. The crude material was added directly to a KP-Sil™column (10 g) in a small amount of CH₂Cl₂ with products separating fromimpurities using stepwise gradients on the Biotage®-Isolera Fourinstrument, monitoring UV Trace at 254/365 nm. The reaction on a 5.0mmol scale yielded 0.55 g of the title intermediate after chromatography(ESS=H:E (1:3), 54% yield). ¹H NMR (D6-DMSO) δ 2.37 (br s, 4H), 3.36 (brs, 2H), 6.60 (d, J=8.1 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 9.06 (br s, 1H),11.62 (br s, 1H). LCMS t=3.9 min, m/z Calcd for C₁₂H₁₃O₃; C₁₂H₁₂NaO₃;C₂₄H₂₅O₆; C₂₄H₂₄NaO₆ 205.09; 227.07; 409.17; 431.15 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 205.16; 227.13; 409.14; 431.12.

INTER- MEDIATE TITLED INTERMEDIATE # NAME R¹ R² R³ 032-Chloro-4-(o-tolylcar- Cl CH₃ H bamoyl)benzenaminium Chloride 042-Fluoro-4-((4-methoxyphenyl)car- F H OCH₃ bamoyl)benzenaminium Chloride05 2-Bromo-4-((4-methoxyphenyl)car- Br H OCH₃ bamoyl)benzenaminiumChloride

Intermediate 03 Preparation of2-Chloro-4-(o-tolylcarbamoyl)benzenaminium Chloride (Intermediate 03)

Step 1, N-Formylation: A mixture of formic acid (18.1 mL, 40 eq, Chem.Pharm. Bull. 2002, 50(7), p. 941-959) and acetic anhydride (11.3 mL, 10eq) were heated to 50° C. for 1 h. After addition of4-amino-3-chlorobenzoic acid (2.1 g, 12.0 mmol, 1.0 eq), the whole washeated to 65° C. for 2 h and cooled to rt. The reaction mixture waspoured into cold H₂O and the precipitates were collected by filtration,washed with H₂O, and dried on the frit. The reaction on a 12.0 mmolscale yielded 2.2 g of 3-chloro-4-formamidobenzoic acid, whitemicrocrystals (mp=227-229° C., 92% yield). LCMS t=4.0 min, m/z Calcd forC₈H₇ClNO₃; C₈H₆ClNNaO₃ 200.01; 221.99 [M+H]⁺; [M+Na]⁺, Found 200.09;222.06.

Step 2, IBCF Method C: 3-Chloro-4-formamidobenzoic acid and o-toluidinewere coupled according to the procedure of Example 04-13; 5.0 mmol scaleyielded 1.0 g of 3-chloro-4-formamido-N-(o-tolyl)benzamide fromprecipitate (69% yield). LCMS t=5.1 min, m/z Calcd for C₁₅H₁₄ClN₂O₂;C₁₅H₁₃ClN₂NaO₂; C₃₀H₂₇Cl₂N₄O₄; C₃₀H₂₆Cl₂N₄NaO₄ 289.07; 311.06; 577.14;599.12 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 289.07; 311.05; 577.14;599.12.

Step 3, N-Deformylation: Acetyl chloride (14 eq, Org. Lett. 2011,13(12), p. 3028-3031) was added to a CH₂Cl₂:MeOH (20 mL, 1:1) mixture at0° C., followed by the 3-chloro-4-formamido-N-(o-tolyl)benzamide (0.87g, 3.0 mmol, 1.0 eq). After warming to rt, HCl salts were collected byfiltration and dried on the frit. The reaction on a 3.0 mmol scaleyielded 0.8 g of 2-chloro-4-(o-tolylcarbamoyl)benzenaminium chloride,the title intermediate (90% yield). ¹H NMR (D6-DMSO) δ 2.20 (s, 3H),4.60 (br s, 3H), 6.84 (d, J=8.4 Hz, 1H), 7.14 (t, J=7.3 Hz, 1H), 7.19(t, J=7.3 Hz, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.70(d, J=8.4 Hz, 1H), 7.89 (s, 1H), 9.56 (s, 1H). ¹³C NMR (D6-DMSO) δ 18.0,114.2, 122.2, 125.7, 125.9, 126.6, 127.8, 128.9, 130.2, 133.7, 136.7,147.7, 164.0. LCMS t=5.0 min, m/z Calcd for C₁₄H₁₄ClN₂O; C₁₄H₁₃ClN₂NaO;C₂₈H₂₆Cl₂N₄NaO₂ 261.08; 283.06; 543.13 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found261.12; 283.09; 543.09.

Intermediate 04 Preparation of2-Fluoro-4-((4-methoxyphenyl)carbamoyl)benzenaminium Chloride(Intermediate 04)

Step 1, N-Formylation: 4-Amino-3-fluorobenzoic acid (5.0 g, 32.3 mmol)was N-formylated according to the procedure of Intermediate 03; thereaction on a 32.3 mmol scale yielded 4.0 g of3-fluoro-4-formamidobenzoic acid, white microcrystals (mp=238-240° C.,68% yield). LCMS t=3.0 min, m/z Calcd for C₈H₇FNO₃; C₈H₆FNNaO₃;C₁₆H₁₃F₂N₂O₆ 184.04; 206.02; 367.07 [M+H]⁺; [M+Na]⁺; [2M+H]⁺, Found184.04; 202.05; 367.07.

Step 2, IBCF Method C: 3-Fluoro-4-formamidobenzoic acid and p-anisidinewere coupled according to the procedure of Example 04-13; 5.0 mmol scaleyielded 1.0 g of 3-fluoro-4-formamido-N-(4-methoxyphenyl)benzamide fromprecipitate (69% yield). LCMS t=4.8 min, m/z Calcd for C₁₅H₁₄FN₂O₃;C₃₀H₂₇F₂N₄O₆; C₃₀H₂₆F₂N₄NaO₆ 289.10; 577.19; 599.17 [M+H]⁺; [2M+H]⁺;[2M+Na]⁺, Found 289.10; 577.19; 599.17.

Step 3, N-Deformylation: The title intermediate was prepared from3-fluoro-4-formamido-N-(4-methoxyphenyl)benzamide according to theprocedure of Intermediate 03; 3.3 mmol scale, with solvent (20 mL),yielded 0.9 g of 2-fluoro-4-((4-methoxyphenyl)carbamoyl)-benzenaminiumchloride (92% yield). LCMS t=4.6 min, m/z Calcd for C₁₄H₁₄FN₂O₂;C₁₄H₁₃FN₂NaO₂; C₂₈H₂₇F₂N₄O₄; C₂₈H₂₆F₂N₄NaO₄ 261.10; 283.09; 521.20;543.18 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 261.10; 283.07; 521.19;543.17.

Intermediate 05 Preparation of2-Bromo-4-((4-methoxyphenyl)carbamoyl)benzenaminium Chloride(Intermediate 05)

Step 1, N-Formylation: 4-Amino-3-bromobenzoic acid (5.0 g, 23.1 mmol)was N-formylated according to the procedure of Intermediate 03; thereaction on a 23.1 mmol scale yielded 3.0 g of3-bromo-4-formamidobenzoic acid, white microcrystals (mp=232-234° C.,79% yield). LCMS t=4.1 min, m/z Calcd for C₈H₇BrNO₃; C₁₆H₁₃Br₂N₂O₆;C₁₆H₁₂Br₂N₂NaO₆ 243.96, 245.96; 488.91; 510.89 [M+H]⁺; [2M+H]⁺;[2M+Na]⁺, Found 243.96, 245.96; 488.91; 510.90.

Step 2, IBCF Method C: 3-Bromo-4-formamidobenzoic acid and p-anisidinewere coupled according to the procedure of Example 04-13; 5.0 mmol scale(exothermic) yielded 0.27 g of3-bromo-4-formamido-N-(4-methoxyphenyl)benzamide from precipitate (15%yield). LCMS t=5.0 min, m/z Calcd for C₁₅H₁₄BrN₂O₃; C₁₅H₁₃BrN₂NaO₃;C₃₀H₂₇Br₂N₄O₆; C₃₀H₂₆Br₂N₄NaO₆ 349.02, 351.02; 371.00, 372.10; 699.03;721.01 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 349.01, 351.01; 370.99,372.99; 699.01; 720.99.

Step 3, N-Deformylation: The title intermediate was prepared from3-bromo-4-formamido-N-(4-methoxyphenyl)benzamide according to theprocedure of Intermediate 03; 0.75 mmol scale, with solvent (10 mL),yielded 0.16 g of 2-bromo-4-((4-methoxyphenyl)carbamoyl)-benzenaminiumchloride (66% yield). LCMS t=4.9 min, m/z Calcd for C₁₄H₁₄BrN₂O₂;C₁₄H₁₃BrN₂NaO₂; C₂₈H₂₇Br₂N₄O₄; C₂₈H₂₆Br₂N₄NaO₄ 321.02, 323.02; 343.01,345.00; 643.04; 665.02 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 321.04,323.04; 343.02, 345.02; 643.07; 665.05.

Intermediate 06 Preparation of 2,6-Dioxocyclohexanecarbonitrile(Intermediate 06)

Step 1: 1,3-Cyclohexandione (2.24 g, 20.0 mmol, J. Med. Chem. 2011, 54,p. 5070-5081) and 1,1-dimethyoxy-N,N-dimethylmethanamine (DMF-DMA, 26.5mL, 200 mmol, 10 eq) were mixed and heated under reflux for 3 h. Thesolvent was removed on the rotovap to provide the product in suitablepurity for the next step. The reaction on a 20.0 mmol scale yielded 3.25g of 2-((dimethylamino)methylene)-cyclohexane-1,3-dione (97% yield). ¹HNMR (CDCl₃) δ 1.85-1.90 (m, 2H), 2.38-2.41 (m, 4H), 3.11 (s, 3H), 3.33(s, 3H), 7.98 (s, 1H). ¹³C NMR (CDCl₃) δ 19.4, 38.1, 44.5, 48.4, 109.2,162.1, 196.1. LCMS t=1.4 min, m/z Calcd for C₉H₁₄NO₂; C₉H₁₃NNaO₂;C₁₈H₂₇N₂O₄; C₁₈H₂₆N₂NaO₄ 168.10; 190.08; 335.20; 357.18 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 168.11; 190.09; 335.21; 357.19.

Step 2: 2-((Dimethylamino)-methylene)cyclohexane-1,3-dione (2.675 g,16.0 mmol, Synthesis 2002, 12, p. 1669-1674) and hydroxylaminehydrochloride (1.15 g, 1.04 eq) were mixed in DI H₂O (1.5 mL) andagitated on a vortex shaker for 30 sec. After 5 min, the product wasisolated by filtration. The reaction on a 16 mmol scale yielded 1.75 gof 6,7-dihydrobenzoisoxazol-4-one hydrochloride (mp=88-90° C., 63%yield). ¹H NMR (CDCl₃) δ 1.70-1.90 (m, 2H), 2.20-2.60 (m, 4H), 8.10 (s,1H), 11.25 (br s, 1H). LCMS t=1.2 min, m/z Calcd for C₇H₈NO₂; C₇H₇NNaO₂;C₁₄H₁₅N₂O₄; C₁₄H₁₄N₂NaO₄ 138.06; 160.04; 275.10; 297.09 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 138.06; 160.04; 275.12; 297.10.

Step 3: 6,7-Dihydrobenzoisoxazol-4-one hydrochloride (2.88 mmol, J. Het.Chem. 1983, 20, p. 645-648) was added to toluene and heated underreflux, for 48 h. The product was filtered from toluene. The reaction ona 2.88 mmol scale yielded 0.3 g of the title intermediate,2,6-dioxocyclohexanecarbonitrile (mp=208-210° C., 76% yield). ¹H NMR(D6-DMSO) δ 1.85-1.91 (m, 2H), 2.44-2.50 (m, 4H). ¹³C NMR (D6-DMSO) δ19.8, 33.0, 91.9, 115.1, 191.7. LCMS t=1.0 min, m/z Calcd for C₇H₈NO₂;C₇H₇NNaO₂; C₁₄H₁₅N₂O₄; C₁₄H₁₄N₂NaO₄ 138.06; 160.04; 275.10; 297.09[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 138.06; 160.04; 275.11;297.10.

Synthesis of Exemplary Species Examples 01-01 to 01-39

Example 01-# TITLE COMPOUND NAME R¹ R² R³ R⁴ 01 Methyl4-((3-oxocyclopent-1-en-1- H H CO₂CH₃ H yl)amino)benzoate 024-((3-Oxocyclopent-1-en-1- H H CONH₂ H yl)amino)benzoamide 033-((2-Methyl-3-oxocyclopent-1-en- H CO₂H H H 1-yl)amino)benzoic acid 04Methyl 3-((2-methyl-3- H CO₂CH₃ H H oxocyclopent-1-en-1-yl)amino)benzoate 05 3-((2-Methyl-3-oxocyclohex-1-en- H CONH₂ H H1-yl)amino)benzamide 06 4-((2-Methyl-3-oxocyclopent-1-en- H H SO₂NH₂ H1-yl)amino)benzenesulfonamide 07 4-((2-Methyl-3-oxocyclopent-1-en- H HCN H 1-yl)amino)benzonitrile 08 3-((3-Bromophenyl)amino)-2- H Br H Hmethylcyclopent-2-enone 09 3-((4-Acetylphenyl)amino)-2- H H COCH₃ Hmethylcyclopent-2-enone 10 2-Chloro-4-((2-methyl-3- H Cl CO₂H Hoxocyclopent-1-en-1- yl)amino)benzoic acid 11 Methyl3-chloro-4-((2-methyl-3- Cl H CO₂CH₃ H oxocyclopent-1-en-1-yl)amino)benzoate 12 3-Methoxy-4-((2-methyl-3- OCH₃ H CO₂H Hoxocyclopent-1-en-1- yl)amino)benzoic acid 13 Methyl2-methoxy-4-((2-methyl-3- H OCH₃ CO₂CH₃ H oxocyclopent-1-en-1-yl)amino)benzoate 14 3-Methyl-4-((2-methyl-3- CH₃ H CO₂H Hoxocyclopent-1-en-1- yl)amino)benzoic acid 15 2-Methoxy-3-((2-methyl-3-OCH₃ CO₂H H H oxocyclopent-1-en-1- yl)amino)benzoic acid 162-Methyl-4-((2-methyl-3- H CH₃ CO₂H H oxocyclopent-1-en-1-yl)amino)benzoic acid 17 2,5-Dichloro-4-((2-methyl-3- Cl H CO₂H Cloxocyclopent-1-en-1- yl)amino)benzoic acid 182-((2-Methyl-3-oxocyclopent-1-en- CONH₂ H H H 1-yl)amino)benzamide 19Methyl 2-((2-methyl-3- CO₂CH₃ H H H oxocyclopent-1-en-1-yl)amino)benzoate 20 Methyl 5-chloro-2-((2-methyl-3- CO₂CH₃ H Cl Hoxocyclopent-1-en-1- yl)amino)benzoate 21 Methyl3-fluoro-4-((2-methyl-3- F H CO₂CH₃ H oxocyclopent-1-en-1-yl)amino)benzoate 22 Methyl 3-bromo-4-((2-methyl-3- Br H CO₂CH₃ Hoxocyclopent-1-en-1- yl)amino)benzoate 23 2-Chloro-6-((2-methyl-3- CO₂HCl H H oxocyclopent-1-en-1- yl)amino)benzoic acid 24 Methyl4-chloro-2-((2-methyl-3- CO₂CH₃ H H Cl oxocyclopent-1-en-1-yl)amino)benzoate 25 4-Chloro-3-((2-methyl-3- Cl H H CO₂Hoxocyclopent-1-en-1- yl)amino)benzoic acid

Example 01-01 Preparation of methyl4-((3-oxocyclopent-1-en-1-yl)amino)benzoate (01-01)

2-methyl-1,3-cyclopentandione (5.0 g, 45.0 mmol) andmethyl-4-aminobenzoate (7.5 g, 1.1 eq) were heated to reflux in toluene.Upon reflux the solution was removed from heating, and p-TSA (cat.) wasadded. The apparatus was equipped with a Dean-Stark condenser andreturned to reflux for 18 h, unless more time was required. The solventwas removed on the rotovap and the subsequent crude material wasrecrystallized to give the title compound as product from the indicatedsolvent(s). The reaction on a 45.0 mmol scale yielded 10.0 g of graymicrocrystals from MeOH/H₂O (mp=210-212° C., 91% yield). ¹H NMR(D6-DMSO) δ 1.59 (s, 3H), 2.24-2.26 (m, 2H), 2.78-2.80 (m, 2H), 3.81 (s,3H), 7.32 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 9.18 (s, 1H). ¹³CNMR (D6-DMSO) δ 8.0, 26.7, 33.4, 52.3, 112.9, 120.8, 123.9, 130.8,145.2, 166.2, 168.2, 203.0. LCMS t=4.8 min, m/z Calcd for C₁₄H₁₆NO₃;C₁₄H₁₅NNaO₃; C₂₈H₃₁N₂O₆; C₂₈H₃₀N₂NaO₆ 246.11; 268.10; 491.22; 513.20[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 246.12; 268.11; 491.24;513.22.

Example 01-02 Preparation of4-((3-oxocyclopent-1-en-1-yl)amino)benzamide (01-02)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-aminobenzamide according to the procedure of Example 01-01; 25.0 mmolscale yielded 5.0 g of yellow microcrystals from H₂O (mp=192-195° C.,87% yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.76 (s,2H), 7.28 (d, J=7.8 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 7.90 (s, 1H), 9.11(s, 1H). LCMS t=2.8 min, m/z Calcd for C₁₃H₁₅N₂O₂; C₁₃H₁₄N₂NaO₂;C₂₆H₂₈N₄NaO₄ 231.11; 253.10; 483.20 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found231.12; 253.11; 483.22.

Example 01-03 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-03)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-aminobenzoic acid according to the procedure of Example 01-01; 30.0mmol scale refluxed for 48 h yielded 5.0 g of white microcrystals fromtoluene (mp=236-238° C., 72% yield). ¹H NMR (D6-DMSO) δ 1.58 (s, 3H),2.23 (s, 2H), 2.70 (s, 2H), 7.46-7.50 (m, 2H), 7.66-7.67 (m, 1H), 7.78(s, 1H), 9.11 (s, 1H), 13.11 (s, 1H). LCMS t=4.4 min, m/z Calcd forC₁₃H₁₄NO₃; C₁₃H₁₃NNaO₃; C₂₆H₂₇N₂O₆; C₂₆H₂₆N₂NaO₆ 232.10; 254.08; 463.19;485.17 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 232.11; 254.09; 463.21;485.19.

Example 01-04 Preparation of methyl3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-04)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 3-benzoate according to the procedure of Example 01-01; 30.0 mmolscale yielded 7.0 g of white microcrystals from EtOAc (mp=133-135° C.,95% yield). ¹H NMR (D6-DMSO) δ 1.57 (s, 3H), 2.22-2.24 (m, 2H), 2.70 (s,2H), 3.86 (s, 3H), 7.49-7.54 (m, 3H), 7.67 (d, J=7.5 Hz, 1H), 7.80 (s,1H), 9.13 (s, 1H). LCMS t=5.0, m/z Calcd for C₁₄H₁₆NO₃; C₂₈H₃₁N₂O₆;C₂₈H₃₀N₂NaO₆ 246.11; 491.22; 513.20 [M+H]⁺; [2M+H]⁺; [2M+Na]⁺, Found246.13; 491.24; 513.22.

Example 01-05 Preparation of3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (01-05)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-aminobenzamide according to the procedure of Example 01-01; 30.0 mmolscale yielded 5.0 g of grey microcrystals from MeOH (mp=269-271° C., 72%yield). ¹H NMR (D6-DMSO) δ 1.57 (s, 3H), 2.21-2.23 (m, 2H), 2.67 (s,2H), 7.37-7.42 (m, 3H), 7.63 (d, J=7.5 Hz, 2H), 7.71 (s, 1H), 8.00 (s,1H), 9.08 (s, 1H). LCMS t=3.1 min, m/z Calcd for C₁₃H₁₅N₂O₂;C₁₃H₁₄N₂NaO₂; C₂₆H₂₉N₄O₄; C₂₆H₂₈N₄NaO₄ 231.11; 253.10; 461.22; 483.20[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 231.12; 253.11; 461.24;483.22.

Example 01-06 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzenesulfonamide (01-06)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andsulfanilamide according to the procedure of Example 01-01; 30.0 mmolscale yielded 7.0 g of yellow microcrystals from THF/H₂O (mp=245-247°C., 88% yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.25-2.26 (m, 2H), 2.78(s, 2H), 7.29 (s, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H),9.22 (s, 1H). LCMS t=2.9 min, m/z Calcd for C₁₂H₁₅N₂O₃S; C₂₄H₂₈N₄NaO₆S₂267.08; 555.13 [M+H]⁺; [2M+Na]⁺, Found 267.09; 555.16.

Example 01-07 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzonitrile (01-07)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-aminobenzonitrile according to the procedure of Example 01-01; 30.0mmol scale yielded 4.0 g of yellow microcrystals from H₂O (mp=204-206°C., 63% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.27 (m, 2H), 2.82(s, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 9.27 (s, 1H).LCMS t=5.3 min, m/z Calcd for C₁₃H₁₃N₂O; C₁₃H₁₂N₂NaO; C₂₆H₂₄N₄NaO₂213.10; 235.08; 447.18 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 213.17; 235.14;447.15.

Example 01-08 Preparation of3-((3-bromophenyl)amino)-2-methylcyclopent-2-enone (01-08)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-bromoaniline according to the procedure of Example 01-01; 50.0 mmolscale yielded 6.1 g of brown microcrystals from EtOAc (mp=291-294° C.,46% yield). ¹H NMR (D6-DMSO) δ 1.58 (s, 3H), 2.22 (s, 2H), 2.69 (s, 2H),7.25-7.31 (m, 3H), 7.45 (s, 1H), 9.04 (s, 1H). LCMS t=5.8 min, m/z Calcdfor C₁₂H₁₃BrNO; C₁₂H₁₂BrNNaO; C₂₄H₂₄Br₂N₂NaO₂ 266.02, 268.02; 288.00,290.00; 555.01 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 266.07, 268.06; 288.04,290.03; 554.98.

Example 01-09 Preparation of3-((4-acetylphenyl)amino)-2-methylcyclopent-2-enone (01-09)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-aminoacetophenone according to the procedure of Example 01-01; 25.0mmol scale yielded 0.5 g of orange microcrystals from toluene(mp=270-273° C., 9% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26 (s,2H), 2.82 (s, 2H), 3.36 (s, 3H), 7.33 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5Hz, 2H), 9.23 (s, 1H). LCMS t=5.2 min, m/z Calcd for C₁₄H₁₆NO₂;C₁₄H₁₅NNaO₂; C₂₈H₃₀N₂NaO₄ 230.12; 252.10; 481.21 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 230.19; 252.16; 481.21.

Example 01-10 Preparation of2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-10)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-amino-2-chlorobenzoic acid according to the procedure of Example01-01; 25.0 mmol scale yielded 4.3 g of yellow needles from acetone(mp=239-241° C., 65% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.27 (s,2H), 2.83 (s, 2H), 7.27 (d, J=6.8 Hz, 1H), 7.38 (s, 1H), 7.84 (d, J=8.6Hz, 1H), 9.21 (s, 1H), 13.1 (s, 1H). LCMS t=5.1 min, m/z Calcd forC₁₃H₁₃ClNO₃; C₁₃H₁₂ClNNaO₃; C₂₆H₂₄Cl₂N₂NaO₆ 266.06; 288.04; 553.09[M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 266.12; 288.09; 553.09.

Example 01-11 Preparation of methyl3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-11)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 4-amino-3-chlorobenzoate according to the procedure of Example01-01; 25.0 mmol scale yielded 3.4 g from EtOAc (49% yield). ¹H NMR(D6-DMSO) δ 1.44 (s, 3H), 2.24-2.26 (m, 2H), 2.54-2.55 (m, 2H), 3.86 (s,3H), 7.42 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 8.98(s, 1H). LCMS t=5.7 min, m/z Calcd for C₁₄H₁₅ClNO₃; C₁₄H₁₄ClNNaO₃;C₂₈H₂₈Cl₂N₂NaO₆ 280.07; 302.06; 581.12 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found280.13; 302.10; 581.12.

Example 01-12 Preparation of3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-12)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-amino-3-methoxybenzoic acid according to the procedure of Example01-01; 25.0 mmol scale yielded 4.8 g of tan needles from EtOH(mp=231-234° C., 74% yield). ¹H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.19-2.21(m, 2H), 2.55-2.56 (m, 2H), 3.89 (s, 3H), 7.28 (d, J=8.5 Hz, 1H),7.55-7.57 (m, 2H), 8.56 (s, 1H), 12.96 (s, 1H). LCMS t=5.1 min, m/zCalcd for C₁₄H₁₆NO₄; C₁₄H₁₅NNaO₄; C₂₈H₃₀N₂NaO₈ 262.11; 284.09; 545.19[M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 262.17; 284.14; 545.19.

Example 01-13 Preparation of methyl2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-13)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 4-amino-2-methoxybenzoate according to the procedure of Example01-01; 25.0 mmol scale yielded 6.8 g of tan microcrystals from toluene(mp=193-196° C., 99% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.26(m, 2H), 2.84 (s, 2H), 3.75 (s, 3H), 3.82 (s, 3H), 6.88 (d, J=8.4 Hz,1H), 6.97 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 9.15 (s, 1H). LCMS t=5.3 min,m/z Calcd for C₁₅H₁₈NO₄; C₁₅H₁₇NNaO₄; C₃₀H₃₄N₂NaO₈ 276.12; 298.11;573.22 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 276.18; 298.15; 573.24.

Example 01-14 Preparation of3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-14)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-amino-3-methylbenzoic acid according to the procedure of Example01-01; 25.0 mmol scale yielded 3.0 g of tan sheets from EtOH(mp=233-236° C., 49% yield). ¹H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.19-2.21(m, 2H), 2.30 (s, 3H), 2.47 (s, 2H), 7.24 (d, J=8.2 Hz, 1H), 7.77 (d,J=8.0 Hz, 1H), 7.85 (s, 1H), 8.74 (s, 1H), 12.88 (s, 1H). LCMS t=5.1min, m/z Calcd for C₁₄H₁₆NO₃; C₁₄H₁₅NNaO₃; C₂₆H₃₀N₂NaO₆ 246.11; 268.10;513.20 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 246.19; 268.15; 513.20.

Example 01-15 Preparation of2-methoxy-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-15)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-amino-2-methoxybenzoic acid according to the procedure of Example01-01; 25.0 mmol scale yielded 4.0 g of grey microcrystals from EtOH(mp=220-223° C., 61% yield). ¹H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.16-2.19(m, 2H), 2.44 (s, 2H), 3.72 (s, 3H), 7.19 (t, J=7.8 Hz, 1H), 7.42 (d,J=7.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 8.72 (s, 1H), 13.03 (s, 1H). ¹³CNMR (D6-DMSO) δ 7.2, 25.3, 32.7, 61.3, 109.1, 123.7, 127.1, 127.7,130.6, 133.7, 153.6, 167.0, 170.3, 202.0. LCMS t=1.2 min, m/z Calcd forC₁₄H₁₆NO₄; C₁₄H₁₅NNaO₄; C₂₈H₃₀N₂NaO₈ 262.11; 284.09; 545.19 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 262.21; 284.18; 545.27.

Example 01-16 Preparation of2-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-16)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-amino-2-methylbenzoic acid according to the procedure of Example01-01; 25.0 mmol scale yielded 3.0 g of black needles from EtOH(mp=213-216° C., 49% yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.23-2.25(m, 2H), 2.52 (s, 3H), 2.78 (s, 2H), 7.11-7.13 (m, 2H), 7.83 (d, J=8.2Hz, 1H), 9.07 (s, 1H), 12.58 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.5, 21.7,26.2, 33.0, 111.8, 118.1, 123.7, 124.4, 131.9, 141.0, 143.2, 168.0,168.3, 202.4. LCMS t=5.1 min, m/z Calcd for C₁₄H₁₆NO₃; C₁₄H₁₅NNaO₃;C₂₆H₃₀N₂NaO₆ 246.11; 268.10; 513.20 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found246.22; 268.19; 513.27.

Example 01-17 Preparation of2,5-dichloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-17)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-amino-2,5-dichlorobenzoic acid according to the procedure of Example01-01; 20.0 mmol scale yielded 5.0 g of yellow needles from EtOH(mp=229-232° C., 82% yield). ¹H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.21 (s,2H), 2.45 (s, 2H), 7.64-7.66 (m, 2H), 8.97 (s, 1H), 13.85 (s, 1H). ¹³CNMR (D6-DMSO) δ 7.5, 25.5, 32.7, 110.4, 126.6, 129.4, 131.5, 134.9,139.1, 165.7, 168.9, 202.8. LCMS t=5.1 min, m/z Calcd for C₁₃H₁₂Cl₂NO₃;C₂₆H₂₂C₁₄N₂NaO₆ 300.02; 623.01 [M+H]⁺; [2M+Na]⁺, Found 300.10; 623.09.

Example 01-18 Preparation of2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (01-18)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andanthranilamide according to the procedure of Example 01-01; 20.0 mmolscale yielded 3.0 g of yellow microcrystal from EtOH (mp=235-238° C.,65% yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.26-2.29 (m, 2H), 2.91 (s,2H), 7.07-7.11 (m, 1H), 7.47-7.49 (m, 2H), 7.75 (s, 1H), 7.78 (d, J=7.9Hz, 1H) 8.25 (s, 1H), 11.14 (s, 1H). ¹³C NMR (D6-DMSO) δ 6.6, 26.3,33.3, 112.2, 119.8, 121.3, 121.8, 129.2, 132.3, 140.9, 168.4, 170.9,201.6. LCMS t=4.3 min, m/z Calcd for C₁₃H₁₅N₂O₂; C₁₃H₁₄N₂NaO₂;C₂₆H₂₉N₄O₄; C₂₆H₂₈N₄NaO₄ 231.11; 253.10; 461.22; 483.20 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 231.11; 253.10; 461.22; 483.20.

Example 01-19 Preparation of methyl2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-19)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl anthranilate according to the procedure of Example 01-01; 20.0mmol scale yielded 4.0 g from EtOAc (82% yield). ¹H NMR (D6-DMSO) δ 1.62(s, 3H), 2.29-2.31 (m, 2H), 2.88 (s, 2H), 3.87 (s, 3H), 7.17 (t, J=7.5Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.97 (d, J=7.9Hz, 1H) 10.11 (s, 1H). ¹³C NMR (D6-DMSO) δ 6.7, 26.3, 33.2, 52.5, 112.7,117.9, 120.9, 122.6, 131.3, 134.3, 141.6, 167.7, 168.3, 201.8. LCMSt=5.3 min, m/z Calcd for C₁₄H₁₆NO₃; C₁₄H₁₅NNaO₃; C₂₈H₃₁N₂O₆;C₂₈H₃₀N₂NaO₆ 246.11; 268.10; 491.22; 513.20 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 246.11; 268.09; 491.22; 513.20.

Example 01-20 Preparation of methyl5-chloro-2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-20)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 5-chloroanthranilate according to the procedure of Example 01-01;5.0 mmol scale yielded 1.0 g of yellow microcrystals from EtOAc(mp=162-165° C., 82% yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.29-2.31(m, 2H), 2.86 (s, 2H), 3.88 (s, 3H), 7.54 (d, J=8.9 Hz, 1H), 7.65 (dd,J=8.9, 2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 9.96 (s, 1H). ¹³C NMR(D6-DMSO) δ 6.8, 26.2, 33.2, 52.8, 113.2, 119.6, 122.9, 126.2, 130.4,133.8, 140.5, 166.6, 167.7, 202.1. LCMS t=5.7 min, m/z Calcd forC₁₄H₁₅ClNO₃; C₁₄H₁₄ClNNaO₃; C₂₈H₂₈Cl₂N₂NaO₆ 280.07; 302.06; 581.12[M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 280.07; 302.05; 581.12.

Example 01-21 Preparation of methyl3-fluoro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-21)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 4-amino-3-fluorobenzoate according to the procedure of Example01-01; 20.0 mmol scale yielded 4.5 g of beige microcrystals from EtOAc(mp=198-201° C., 85% yield). ¹H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.24-2.26(m, 2H), 2.57 (s, 2H), 3.86 (s, 3H), 7.40-7.44 (m, 1H), 7.77-7.79 (m,2H), 9.09 (s, 1H). LCMS t=5.0 min, m/z Calcd for C₁₄H₁₅FNO₃;C₁₄H₁₄FNNaO₃; C₂₈H₂₉F₂N₂O₆; C₂₈H₂₈F₂N₂NaO₆ 264.10; 286.09; 527.20;549.18 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 264.10; 286.08; 527.20;549.18.

Example 01-22 Preparation of methyl3-bromo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-22)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 4-amino-3-bromobenzoate according to the procedure of Example01-01; 20.0 mmol scale yielded 4.0 g of white microcrystals from EtOAc(mp=155-158° C., 62% yield). ¹H NMR (D6-DMSO) δ 1.43 (s, 3H), 2.23-2.25(m, 2H), 2.50-2.53 (m, 2H), 3.86 (s, 3H), 7.44 (d, J=8.3 Hz, 1H),7.94-7.95 (m, 1H), 8.17 (d, J=1.4 Hz, 1H), 8.91 (s, 1H). ¹³C NMR(D6-DMSO) δ 7.8, 25.9, 32.7, 52.4, 111.4, 119.1, 126.9, 127.6, 129.1,133.5, 142.5, 164.6, 168.2, 203.0. LCMS t=5.2 min, m/z Calcd forC₁₄H₁₅BrNO₃; C₁₄H₁₄BrNNaO₃; C₂₈H₂₉Br₂N₂O₆; C₂₈H₂₈Br₂N₂NaO₆ 324.02,326.02; 346.01, 348.00; 649.04; 671.02 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 324.02, 326.02; 346.00, 348.00; 649.04; 671.02.

Example 01-23 Preparation of2-chloro-6-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-23)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and6-chloroanthranilic acid according to the procedure of Example 01-01;20.0 mmol scale yielded 3.0 g of white microcrystals from EtOH(mp=277-280° C., 56% yield). ¹H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.14-2.16(m, 2H), 2.36-2.38 (m, 2H), 7.31 (dd, J=6.5, 2.1 Hz, 1H), 7.45-7.48 (m,2H), 8.95 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.1, 25.3, 32.6, 109.1, 127.0,127.4, 129.6, 130.7, 132.9, 137.6, 166.3, 170.3, 202.2. LCMS t=4.5 min,m/z Calcd for C₁₃H₁₃ClNO₃; C₂₆H₂₅Cl₂N₂O₆ 266.06; 531.11 [M+H]⁺; [2M+H]⁺,Found 266.06; 531.11.

Example 01-24 Preparation of methyl4-chloro-2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-24)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 4-chloroanthranilate according to the procedure of Example 01-01;20.0 mmol scale yielded 4.6 g of yellow sheets from EtOAc (mp=167-170°C., 82% yield). ¹H NMR (CDCl3) δ 1.82 (s, 3H), 2.53-2.55 (m, 2H),3.02-3.03 (m, 2H), 3.95 (s, 3H), 6.98 (dd, J=8.6, 1.7 Hz, 1H), 7.37 (d,J=1.6 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 10.67 (s, 1H). ¹³C NMR (CDCl3) δ7.2, 27.8, 33.9, 52.8, 113.9, 117.2, 117.9, 121.4, 133.4, 140.7, 144.3,166.8, 168.3, 204.0. LCMS t=5.7 min, m/z Calcd for C₁₄H₁₅ClNO₃;C₁₄H₁₄ClNNaO₃; C₂₈H₂₉Cl₂N₂O₆; C₂₈H₂₈Cl₂N₂NaO₆ 280.07; 302.06; 559.14;581.12 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 280.07; 302.05; 559.14;581.12.

Example 01-25 Preparation of4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-25)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-amino-4-chlorobenzoic acid according to the procedure of Example01-01; 20.0 mmol scale yielded 5.0 g of white microcrystals from EtOH(mp=272-275° C., 94% yield). ¹H NMR (D6-DMSO) δ 1.42 (s, 3H), 2.20-2.22(m, 2H), 2.41-2.43 (m, 2H), 7.69 (d, J=7.9 Hz, 1H), 7.79-7.81 (m, 2H),8.97 (s, 1H), 13.31 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.5, 25.7, 32.6, 109.7,127.8, 128.7, 130.2, 134.5, 136.9, 166.1, 169.2, 202.6. LCMS t=4.3 min,m/z Calcd for C₁₃H₁₃ClNO₃; C₂₆H₂₅Cl₂N₂O₆ 266.06; 531.11 [M+H]⁺; [2M+H]⁺,Found 266.06; 531.07.

Example 01-26 Preparation of2-methyl-3-(naphthalen-1-ylamino)cyclopent-2-enone (01-26)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and1-naphthylamine according to the procedure of Example 01-01; 12.5 mmolscale yielded 1.0 g of tan needles from EtOAc (mp=166-168° C., 34%yield). ¹H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.15-2.16 (m, 2H), 2.38 (s,2H), 7.42 (d, J=7.1 Hz, 1H), 7.52-7.61 (m, 3H), 7.87 (d, J=8.1 Hz, 1H),8.00 (t, J=8.6 Hz, 2H), 9.26 (s, 1H). LCMS t=5.4 min, m/z Calcd forC₁₆H₁₆NO; C₁₆H₁₅NNaO; C₃₂H₃₁N₂O₂; C₃₂H₃₀N₂NaO₂ 238.12; 260.11; 475.24;497.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 238.14; 260.12; 475.26;497.24.

Example 01-27 Preparation of2-methyl-3-(naphthalen-2-ylamino)cyclopent-2-enone (01-27)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and2-naphthylamine according to the procedure of Example 01-01; 6.0 mmolscale yielded 0.2 g of yellow needles from EtOAc (mp=248-250° C., 14%yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.23-2.25 (m, 2H), 2.77-2.78(m, 2H), 7.42-7.51 (m, 3H), 7.71 (s, 1H), 7.85-7.90 (m, 3H), 9.16 (s,1H). LCMS t=5.5 min, m/z Calcd for C₁₆H₁₆NO; C₁₆H₁₅NNaO; C₃₂H₃₁N₂O₂;C₃₂H₃₀N₂NaO₂ 238.12; 260.11; 475.24; 497.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 238.13; 260.12; 475.26; 497.24.

Exam- ple TITLE COMPOUND 01-# NAME X Y Z 28 2-Methyl-3-(pyridin-2- N CHCH ylamino)cyclopent-2-enone 29 2-Methyl-3-(pyridin-3- CH N CHylamino)cyclopent-2-enone 30 2-Methyl-3-(pyridin-4- CH CH Nylamino)cyclopent-2-enone

Example 01-28 Preparation of2-methyl-3-(pyridin-2-ylamino)cyclopent-2-enone (01-28)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and2-aminopyridine according to the procedure of Example 01-01; 30.0 mmolscale yielded 0.6 g of yellow sheets from EtOAc (mp=163-165° C., 11%yield). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 2.23 (s, 2H), 3.18 (s, 2H),6.96 (d, J=5.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.69-7.71 (m, 1H), 8.23(s, 1H), 9.32 (s, 1H). LCMS t=4.4 min, m/z Calcd for C₁₁H₁₃N₂O;C₁₁H₁₂N₂NaO; C₂₂H₂₅N₄O₂; C₂₂H₂₄N₄NaO₂ 189.10; 211.08; 377.20; 399.18[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 189.11; 211.09; 377.21;399.20.

Example 01-29 Preparation of2-methyl-3-(pyridin-3-ylamino)cyclopent-2-enone (01-29)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-aminopyridine according to the procedure of Example 01-01; 30.0 mmolscale yielded 1.6 g of grey microneedles from EtOAc (mp=133-135° C., 28%yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.22 (s, 2H), 2.66 (s, 2H),7.38 (dd, J=7.7, 4.7 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 8.32 (d, J=3.6 Hz,1H), 8.51 (s, 1H), 9.07 (s, 1H). LCMS t=1.4 min, m/z Calcd forC₁₁H₁₃N₂O; C₁₁H₁₂N₂NaO; C₂₂H₂₅N₄O₂; C₂₂H₂₄N₄NaO₂ 189.10; 211.08; 377.20;399.18 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 189.11; 211.09; 377.22;399.20.

Example 01-30 Preparation of2-methyl-3-(pyridin-4-ylamino)cyclopent-2-enone (01-30)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-aminopyridine according to the procedure of Example 01-01; 20.0 mmolscale for 72 h yielded 0.02 g of yellow microcrystals from EtOAc(mp=203-205° C., 1% yield). ¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.28-2.29(m, 2H), 2.90 (s, 2H), 7.20 (d, J=4.9 Hz, 2H), 8.38 (s, 2H), 9.15 (s,1H). LCMS t=1.4 min, m/z Calcd for C₁₁H₁₃N₂O 189.10 [M+H]⁺, Found189.12.

Example 01-31 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(pyridin-2-yl)benzenesulfonamide(01-31)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and4-amino-N-(2-pyridinyl)benzenesulfonamide according to the procedure ofExample 01-01; 10.0 mmol scale yielded 2.0 g of yellow microcrystalsfrom H₂O (mp=230-233° C., 58% yield). ¹H NMR (D6-DMSO) δ 1.58 (s, 3H),2.23-2.25 (m, 2H), 2.77 (s, 2H), 6.88 (t, J=5.5 Hz, 1H), 7.15 (d, J=8.5Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.80 (d, J=8.4Hz, 1H), 9.18 (s, 1H). LCMS t=4.9 min, m/z Calcd for C₁₇H₁₈N₃O₃S;C₁₇H₁₇N₃NaO₃S; C₃₄H₃₄N₆NaO₆S₂ 344.11; 366.09; 709.19 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 344.11; 366.08; 709.16.

Example 01-32 Preparation of tert-Butyl4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)piperidine-1-carboxylate(01-32)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andtert-butyl 4-aminopiperidine-1-carboxylate according to the procedure ofExample 01-01; 5.0 mmol scale yielded 0.6 g of grey microcrystals fromH₂O (mp=189-191° C., 41% yield). ¹H NMR (D6-DMSO) δ 1.40-1.46 (m, 14H),1.76 (d, J=11.6 Hz, 2H), 2.10-2.11 (m, 2H), 2.51 (d, J=5.8 Hz, 2H), 2.73(s, 2H), 2.65-2.90 (m, 2H), 3.52 (s, 1H), 3.94 (s, 2H), 6.88 (d, J=8.3Hz, 1H). LCMS t=5.6 min, m/z Calcd for C₁₆H₂₇N₂O₃; C₁₆H₂₆N₂NaO₃;C₃₂H₅₂N₄NaO₆ 295.20; 317.18; 611.38 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found295.26; 317.20; 611.35.

Example 01-33 Preparation oftrans-(1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxylicacid (01-33)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andtrans-(1R,4R)-4-aminocyclohexanecarboxylic acid according to theprocedure of Example 01-01; 25.0 mmol scale yielded 4.0 g of whitemicroneedles from H₂O (mp=236-238° C., 67% yield). ¹H NMR (D6-DMSO) δ1.35-1.45 (m, 7H), 1.84 (d, J=9.3 Hz, 2H), 1.87-1.93 (m, 1H), 2.10 (s,2H), 2.50 (s, 2H), 3.34 (br s, 2H), 6.88 (d, J=7.6 Hz, 1H), 12.1 (s,1H). LCMS t=4.7 min, m/z Calcd for C₁₃H₂₀NO₃; C₁₃H₁₉NNaO₃; C₂₆H₃₉N₂O₆;C₂₆H₃₈N₂NaO₆ 238.14; 260.13; 475.28; 497.26 [M+H]⁺; [M+Na]⁺; [2M+H]²+;[2M+Na]⁺, Found 238.21; 260.18; 475.26; 497.24.

Example 01-34 Preparation ofcis-(1S,4S)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxylicacid (01-34)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andcis-(1S,4S)-4-aminocyclohexanecarboxylic acid according to the procedureof Example 01-01; 25.0 mmol scale yielded 2.6 g of tan microneedles fromH₂O (mp=233-235° C., 44% yield). ¹H NMR (D6-DMSO) δ 1.46-1.52 (m, 7H),1.66 (d, J=8.8 Hz, 2H), 2.03-2.11 (m, 3H), 2.51 (s, 2H), 3.38 (br s,2H), 6.94 (d, J=7.6 Hz, 1H), 12.25 (s, 1H). LCMS t=4.9 min, m/z Calcdfor C₁₃H₂₀NO₃; C₁₃H₁₉NNaO₃; C₂₆H₃₉N₂O₆; C₂₆H₃₈N₂NaO₆ 238.14; 260.13;475.28; 497.26 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 238.21; 260.18;475.26; 497.24.

Example 01-35 Preparation of4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (01-35)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and4-aminobenzamide according to the procedure of Example 01-01; 12.5 mmolscale yielded 1.0 g of tan microsheets from CH₂Cl₂/hexanes (mp=221-223°C., 33% yield). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.81 (t, J=5.7 Hz, 2H),2.24 (t, J=5.8 Hz, 2H), 2.53 (s, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.28 (s,1H), 7.83 (d, J=8.1 Hz, 2H), 7.89 (s, 1H), 8.36 (s, 1H). LCMS t=3.9 min,m/z Calcd for C₁₄H₁₇N₂O₂; C₁₄H₁₆N₂NaO₂; C₂₈H₃₂N₄NaO₄ 245.13; 267.11;511.23 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 245.15; 267.12; 511.26.

Example 01-# TITLE COMPOUND NAME R¹ R² R³ R⁴ 364-Chloro-3-((2-methyl-3-oxocyclohex-1- Cl H H CO₂H en-1-yl)amino)benzoicacid 37 2-(3-((2-Methyl-3-oxocyclohex-1-en-1- H CH₂CO₂H H Hyl)amino)phenyl)acetic acid 38 2-(4-((2-Methyl-3-oxocyclohex-1-en-1- H HCH₂CO₂H H yl)amino)phenyl)acetic acid 393-((2-Methyl-3-oxocyclohex-1-en-1- CF₃ H H CO₂Hyl)amino)-4-(trifluoromethyl)benzoic acid 404-((2-Methyl-3-oxocyclohex-1-en-1- CF₃ H CO₂H Hyl)amino)-4-(trifluoromethyl)benzoic acid

Example 01-36 Preparation of4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid (01-36)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-amino-4-chlorobenzoic acid according to the procedure of Example01-01; 20.0 mmol scale yielded 5.0 g of tan microcrystals from EtOH(mp=232-235° C., 89% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.76-1.80(m, 2H), 2.21 (t, J=6.2 Hz, 2H), 2.26 (t, J=5.6 Hz, 2H), 7.66 (dd,J=8.3, 1.0 Hz, 1H), 7.12 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.09 (s, 1H),13.29 (br s, 1H). ¹³C NMR (D6-DMSO) δ 9.2, 21.0, 27.2, 36.3, 107.9,127.4, 128.8, 130.1, 130.3, 134.8, 137.5, 158.2, 166.2, 194.9. LCMSt=4.7 min, m/z Calcd for C₁₄H₁₅ClNO₃; C₂₈H₂₈Cl₂N₂NaO₆ 280.07; 581.12[M+H]⁺; [2M+Na]⁺, Found 280.06; 581.11.

Example 01-37 Preparation of2-(3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)acetic acid (01-37)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-aminophenylacetic acid according to the procedure of Example 01-01;2.5 mmol scale yielded 0.25 g of orange microcrystals from EtOH(mp=203-207° C., 39% yield). ¹H NMR (D6-DMSO) δ 1.67 (s, 3H), 2.20 (t,J=6.4 Hz, 2H), 2.43 (t, J=5.6 Hz, 2H), 3.56 (s, 2H), 6.99-7.02 (m, 3H),7.27 (t, J=7.9 Hz, 1H), 8.18 (s, 1H), 12.38 (br s, 1H). ¹³C NMR(D6-DMSO) δ 9.6, 22.2, 27.8, 36.9, 41.01, 107.5, 123.00, 125.6, 125.7,129.0, 136.2, 140.2, 158.6, 173.0, 194.8. LCMS t=4.4 min, m/z Calcd forC₁₅H₁₈NO₃; C₁₅H₁₇NNaO₃; C₃₀H₃₄N₂NaO₆ 260.13; 282.11; 541.23 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 260.11; 282.09; 541.19.

Example 01-38 Preparation of2-(4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)acetic acid (01-38)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and4-aminophenylacetic acid according to the procedure of Example 01-01;20.0 mmol scale yielded 3.6 g of brown sheets from EtOH (mp=215-219° C.,69% yield). ¹H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.75-1.78 (m, 2H), 2.19 (t,J=6.4 Hz, 2H), 2.42 (t, J=5.7 Hz, 2H), 3.55 (s, 2H), 7.06 (d, J=8.3 Hz,2H), 7.22 (d, J=8.3 Hz, 2H), 8.16 (s, 1H), 12.31 (br s, 1H). ¹³C NMR(D6-DMSO) δ 9.5, 22.1, 27.7, 36.8, 40.5, 107.0, 124.9, 130.2, 131.4,138.8, 158.9, 173.2, 194.6. LCMS t=4.3 min, m/z Calcd for C₁₅H₁₈NO₃;C₁₅H₁₇NNaO₃; C₃₀H₃₄N₂NaO₆ 260.13; 282.11; 541.23 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 260.11; 282.09; 541.19.

Example 01-39 Preparation of3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-4-(trifluoromethyl)benzoicacid (01-39)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-amino-4-(trifluoromethyl)benzoic acid according to the procedure ofExample 01-01; 2.5 mmol scale yielded 0.5 g of tan microcrystals fromEtOH/EtOAc (mp=209-212° C., 64% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H),1.73-1.76 (m, 2H), 2.20-2.25 (m, 4H), 7.11 (d, J=7.7 Hz, 1H), 7.47 (d,J=7.8 Hz, 1H), 7.81 (s, 1H), 8.26 (s, 1H). LCMS t=4.6 min, m/z Calcd forC₁₅H₁₅F₃NO₃; C₃₀H₂₈F₆N₂NaO₆ 314.10; 649.17 [M+H]⁺; [2M+Na]⁺, Found314.09; 649.12.

Example 01-40 Preparation of4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-4-(trifluoromethyl)benzoicacid (01-40)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and4-amino-3-(trifluoromethyl)benzoic acid according to the procedure ofExample 01-01; 20.0 mmol scale yielded 2.5 g of tan microneedles fromEtOH (mp=229-231° C., 40% yield). ¹H NMR (D6-DMSO) δ 1.53 (s, 3H),1.78-1.81 (m, 2H), 2.24 (t, J=6.2 Hz, 2H), 2.36-2.40 (m, 2H), 7.36 (d,J=8.3 Hz, 1H), 7.88 (s, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.18 (s, 1H), 13.36(br s, 1H). ¹³C NMR (D6-DMSO) δ 10.1, 21.3, 28.4, 36.9, 111.5, 123.7(J_(CF)=28.6 Hz), 123.8 (J_(CF)=274.0 Hz), 127.5, 128.0, 128.6, 134.3,143.3, 157.6, 166.2, 196.1. LCMS t=4.7 min, m/z Calcd for C₁₅H₁₅F₃NO₃;C₁₅H₁₄F₃NNaO₃; C₃₀H₂₈F₆N₂NaO₆ 314.10; 336.08; 649.17 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 314.08; 336.06; 649.13.

Example 01-41 Preparation of6-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-2-naphthoic acid (01-41)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and6-amino-2-naphthoic acid according to the procedure of Example 01-01;20.0 mmol scale yielded 2.7 g of brown microcrystals from EtOH(mp=259-263° C., 46% yield). ¹H NMR (D6-DMSO) δ 1.73 (s, 3H), 1.83-1.86(m, 2H), 2.27-2.30 (m, 2H), 2.61-2.63 (m, 2H), 7.42 (d, J=8.7 Hz, 1H),7.56 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 8.06 (d,J=8.8 Hz, 1H), 8.52 (s, 1H), 8.55 (s, 1H), 12.97 (br s, 1H). ¹³C NMR(D6-DMSO) δ 10.1, 22.2, 28.2, 37.0, 109.9, 118.7, 124.6, 126.2, 127.0,127.7, 129.1, 130.4, 130.7, 136.0, 140.5, 157.7, 167.9, 195.5. LCMSt=4.7 min, m/z Calcd for C₁₈H₁₈NO₃; C₃₆H₃₅N₂O₆; C₃₆H₃₄N₂NaO₆ 296.13;591.25; 613.23 [M+H]⁺; [2M+H]⁺; [2M+Na]⁺, Found 296.15; 591.27; 613.25.

Example 01-# TITLE COMPOUND NAME R¹ R² R³ R⁴ 42N-(4-Chloro-3-((2-methyl-3- Cl H H NAcoxocyclopent-1-en-1-yl)amino)phenyl)- acetamide 43 Methyl3-iodo-4-((2-methyl-3- I H CO₂CH₃ Hoxocyclopent-1-en-1-yl)amino)benzoate 442-Chloro-3-((2-methyl-3-oxocyclopent-1- Cl CO₂H H Hen-1-yl)amino)benzoic acid 45 3-((2-Methyl-3-oxocyclopent-1-en-1- HSO₂NH₂ H H yl)amino)benzenesulfonamide 464-Chloro-3-((2-methyl-3-oxocyclopent-1- Cl H SO₂NH₂ Hen-1-yl)amino)benzene-sulfonamide

Example 01-42 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-acetamide(01-42)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andN-(3-amino-4-chlorophenyl)acetamide according to the procedure ofExample 01-01; 20.0 mmol scale yielded 5.5 g (99% yield) of tanmicrocrystals. A portion was recrystallized from EtOH:EtOAc (1:1.1)(mp=265-268° C., 50% recovery). ¹H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.05(s, 3H), 2.18-2.21 (m, 2H), 2.40-2.41 (m, 2H), 7.41 (dd, J=8.7, 2.3 Hz,1H), 7.45 (d, J=8.8 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 8.86 (s, 1H), 10.13(s, 1H). ¹³C NMR (D6-DMSO) δ 7.4, 24.1, 25.6, 32.6, 109.3, 117.8, 118.4,123.3, 129.7, 136.6, 138.7, 168.7, 169.5, 202.4. LCMS t=4.3 min, m/zCalcd for C₁₄H₁₆ClN₂O₂; C₁₄H₁₅ClN₂NaO₂; C₂₈H₃₁Cl₂N₄O₄; C₂₈H₃₀Cl₂N₄NaO₄279.09; 301.07; 557.17; 579.15 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found279.11; 301.09; 557.13; 579.11.

Example 01-43 Preparation of methyl3-iodo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-43)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andmethyl 3-iodo-4-aminobenzoate according to the procedure of Example01-01; 10 mmol scale yielded 1.7 g of white prisms from EtOAc(mp=178-180° C., 46% yield). ¹H NMR (D6-DMSO) δ 1.43 (s, 3H), 2.21-2.23(m, 2H), 2.44-2.47 (m, 2H), 3.86 (s, 3H), 7.41 (d, J=8.3 Hz, 1H), 7.96(dd, J=8.3, 1.8 Hz, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.86 (s, 1H). ¹³C NMR(D6-DMSO) δ 7.7, 25.9, 32.7, 52.4, 97.7, 110.5, 126.7, 128.1, 129.8,139.6, 145.7, 164.5, 168.5, 202.6. LCMS t=4.6 min, m/z Calcd forC₁₄H₁₅INO₃; C₁₄H₁₄INNaO₃; C₂₈H₂₈I₂N₂NaO₆ 372.01; 393.99; 764.99 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 372.04; 393.96; 764.95.

Example 01-44 Preparation of2-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(01-44)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-amino-2-chlorobenzoic acid according to the procedure of Example01-01; 2.5 mmol scale yielded 415 mg of white microneedles from EtOH(mp=230-232° C., 62% yield). ¹H NMR (D6-DMSO) δ 1.46 (s, 3H), 2.18-2.02(m, 2H), 2.37-2.40 (m, 2H), 7.44 (t, J=7.8 Hz, 1H), 7.54 (dd, J=7.9, 1.6Hz, 1H), 7.62 (dd, J=7.7, 1.6 Hz, 1H), 8.93 (s, 1H), 13.53 (br s, 1H).¹³C NMR (D6-DMSO) δ 7.3, 25.4, 32.6, 109.4, 127.4, 127.7, 128.3, 130.8,133.5, 137.7, 166.9, 169.7, 202.3. LCMS t=1.8 min, m/z Calcd forC₁₃H₁₃ClNO₃; C₁₃H₁₂ClNNaO₃; C₂₆H₂₄Cl₂N₂NaO₆ 266.06; 288.04; 553.09[M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 266.09; 288.06; 553.03.

Example 01-45 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzenesulfonamide (01-45)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-aminobenzenesulfonamide according to the procedure of Example 01-01;5.0 mmol scale yielded 600 mg of light brown microcrystals from H₂O(mp=223-225° C., 45% yield). ¹H NMR (D6-DMSO) δ 1.58 (s, 3H), 2.22-2.27(m, 2H), 2.68-2.75 (m, 2H), 7.40-7.47 (m, 3H), 7.53 (d, J=5.2 Hz, 2H),7.65 (s, 1H), 9.22 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.5, 25.8, 32.9, 111.1,119.0, 120.4, 125.0, 129.8, 140.5, 144.9, 168.6, 202.3. LCMS t=2.6 min,m/z Calcd for C₁₂H₁₅N₂O₃S; C₁₂H₁₄N₂NaO₃S; C₂₄H₂₉N₄O₆S₂; C₂₄H₂₈N₄NaO₆S₂267.083; 289.062; 533.152; 555.135 [M+H]⁺; [2M+H]⁺; [2M+H]⁺; [2M+Na]⁺,Found 267.083; 289.061; 533.151; 555.133.

Example 01-46 Preparation of4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzene-sulfonamide(01-46)

The title compound was prepared from 2-methyl-1,3-cyclopentandione and3-amino-4-chlorobenzenesulfonamide according to the procedure of Example01-01; 5.0 mmol scale yielded 800 mg of light brown microcrystals fromH₂O (mp=223-225° C., 53% yield). ¹H NMR (D6-DMSO) δ 1.42 (s, 3H),2.20-2.28 (m, 2H), 2.45-2.49 (m, 2H), 7.55 (s, 2H), 7.66 (dd, J=8.2, 2.1Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 9.07 (s, 1H).¹³C NMR (D6-DMSO) δ 7.8, 25.8, 32.7, 110.4, 123.9, 124.8, 130.5, 132.8,137.2, 143.4, 168.8, 202.9. LCMS t=3.4 min, m/z Calcd for C₁₂H₁₅ClN₂O₃S;C₁₂H₁₄ClN₂NaO₃S; C₂₄H₂₉Cl₂N₄O₆S₂; C₂₄H₂₈Cl₂N₄NaO₆S₂ 301.041; 323.023;601.075; 623.057 [M+H]⁺; [2M+H]⁺; [2M+H]⁺; [2M+Na]⁺, Found 301.040;323.021; 601.071; 623.056.

Exam- ple TITLE COMPOUND 01-# NAME R¹ R² R³ R⁴ 47N-(4-Chloro-3-((2-methyl-3- Cl H H NAc oxocyclopent-1-en-1-yl)amino)phenyl)-acetamide 48 Methyl 3-iodo-4-((2-methyl-3- Br H H CO₂Hoxocyclopent-1-en-1- yl)amino)benzoate

Example 01-47 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-acetamide(01-47)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andN-(4-amino-3-chlorophenyl)acetamide according to the procedure ofExample 01-01; 10.0 mmol scale yielded 2.9 g of pale orangemicrocrystals from EtOAc (mp=234-236° C., 99% yield). ¹H NMR (D6-DMSO) δ1.64 (s, 3H), 1.75-1.79 (m, 2H), 2.05 (s, 3H), 2.18-2.24 (m, 4H),7.42-7.46 (m, 2H), 7.58 (d, J=1.9 Hz, 1H), 8.04 (s, 1H), 10.12 (s, 1H).¹³C NMR (D6-DMSO) δ 9.0, 21.1, 24.0, 27.0, 36.3, 107.1, 117.7, 118.8,123.9, 129.7, 137.1, 138.8, 158.8, 168.6, 194.4. LCMS t=4.5 min, m/zCalcd for C₁₅H₁₈ClN₂O₂; C₁₅H₁₇ClN₂NaO₂; C₃₀H₃₅Cl₂N₄O₄; C₃₀H₃₄Cl₂N₂NaO₄293.11; 315.09; 585.20; 607.19 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found293.13; 315.10, 585.16; 607.15.

Example 01-48 Preparation of4-bromo-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid (01-48)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-amino-4-bromobenzoic acid according to the procedure of Example 01-01;10.0 mmol scale yielded 2.9 g of white microneedles from EtOH(mp=265-267° C., 89% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 1.75-1.80(m, 2H), 2.18-2.23 (m, 4H), 7.69-7.72 (m, 2H), 7.84 (d, J=8.1 Hz, 1H),8.07 (s, 1H), 13.31 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.2, 21.1, 27.2, 36.4,107.5, 126.9, 127.9, 129.2, 131.0, 133.3, 139.1, 158.1, 166.3, 194.8.LCMS t=4.2 min, m/z Calcd for C₁₄H₁₅BrNO₃; C₁₄H₁₄BrNNaO₃;C₂₈H₂₈Br₂N₂NaO₆ 324.02, 326.02; 346.01, 348.00; 671.02 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 324.03, 326.02; 345.99, 347.99; 670.96.

Exam- ple TITLE COMPOUND 01-# NAME X Y 493-[(3-Chloropyridin-2-yl)amino]-2- N CH methylcyclohex-2-en-1-one 503-[(3-Chloropyrazin-2-yl)amino]-2- N N methylcyclohex-2-en-1-one

Example 01-49 Preparation of3-[(3-chloropyridin-2-yl)amino]-2-methylcyclohex-2-en-1-one (01-49)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-chloropyridin-2-amine according to the procedure of Example 01-01(mp=113-115° C.). ¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.84 (quin, J=6.4 Hz,2H), 2.28 (t, J=6.1 Hz, 2H), 2.67-2.80 (m, 2H), 7.07 (dd, J=8.5, 4.9 Hz,1H), 7.91 (s, 1H), 7.93 (d, J=6.1 Hz, 1H), 8.25 (d, J=4.9 Hz, 1H). ¹³CNMR (D6-DMSO) δ ppm 9.4, 21.3, 28.1, 36.7, 113.6, 119.2, 120.8, 138.2,146.3, 149.7, 155.6, 196.2. LCMS t=4.3 min, m/z Calcd for C₁₂H₁₄ClN₂O;C₁₂H₁₃ClN₂NaO; C₂₄H₂₆Cl₂N₄NaO₂ 237.080; 259.061; 495.133 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 237.080; 259.060; 495.131.

Example 01-50 Preparation of3-[(3-chloropyrazin-2-yl)amino]-2-methylcyclohex-2-en-1-one (01-50)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-chloropyrazin-2-amine according to the procedure of Example 01-01(mp=116-118° C.). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 1.87 (quin, J=6.1 Hz,2H), 2.32 (t, J=6.1 Hz, 2H), 2.71-2.76 (m, 2H), 8.00 (d, J=2.4 Hz, 1H),8.18 (s, 1H), 8.28 (d, J=2.4 Hz, 1H). ¹³C NMR (D6-DMSO) δ 10.6, 21.6,28.8, 37.2, 118.6, 135.9, 137.9, 141.3, 147.8, 154.3, 197.5. LCMS t=4.1min, m/z Calcd for C₁₁H₁₃ClN₃O; C₁₁H₁₂ClN₃NaO; C₂₂H₂₄Cl₂N₆NaO₂ 238.075;260.060; 497.120 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 238.075; 260.056;497.122.

Example 01-51 Preparation of3-[(3-chloropyridin-4-yl)amino]-2-methylcyclohex-2-en-1-one (01-51)

3-amino-2-methylcyclohex-2-enone (500 mg, 4 mmol),4-bromo-3-chloropyridine (950 mg, 5 mmol), palladium acetate (90 mg, 0.4mmol), BINAP (197 mg, 0.8 mmol), cesium carbonate (2.6 g, 8 mmol) andtoluene (10 mL) were combined in a sealed flask and heated at 100° C.,for 18 h. At rt, the mixture was filtered and the filtrate was dilutedwith EtOAc (30 mL), washed with brine (3×10 mL), dried with Na₂SO₄. Thecrude was purified by HPLC to afford the title compound (140 mg, 15%yield, white microcrystal, mp=135-138° C.). ¹H NMR (D6-DMSO) δ 1.46 (s,3H), 1.83-1.88 (m, 2H), 2.31 (t, J=6.7 Hz, 2H), 2.53-2.57 (m, 2H), 6.84(d, J=6.1 Hz, 1H), 8.06 (s, 1H), 8.29 (d, J=6.1 Hz, 1H), 8.48 (s, 1H).¹³C NMR (D6-DMSO) δ 10.9, 20.6, 28.7, 36.7, 115.7, 117.1, 121.2, 144.7,148.3, 148.3, 149.2, 154.4, 197.0. LCMS t=1.9 min, m/z Calcd forC₁₂H₁₄ClN₂O; C₁₂H₁₃ClN₂NaO 237.080; 259.061 [M+H]⁺; [2M+H]⁺, Found237.080; 259.180.

Exam- ple TITLE COMPOUND 01-# NAME R¹ R² R³ 523-[(2-Methyl-3-oxocyclohex-1-en-1- H H CO₂H yl)amino]naphthalene-1-carboxylic acid 53 5-Chloro-6-[(2-methyl-3-oxocyclohex- Cl CO₂H H1-en-1-yl)amino]naphthalene-2- carboxylic acid

Example 01-52 Preparation of3-[(2-methyl-3-oxocyclohex-1-en-1-yl)amino]naphthalene-1-carboxylic acid(01-52)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-amino-1-naphthoic acid according to the procedure of Example 01-01;4.0 mmol scale refluxed for 48 h yielded 1.2 g of crude filtered fromtoluene (97% yield), brown microcrystals were obtained after acetonetitration (mp=270-272° C.). ¹H NMR (D6-DMSO) δ 1.71 (s, 3H), 1.81-1.85(m, 2H), 2.25-2.28 (m, 2H), 2.57-2.50 (m, 2H), 7.52-7.57 (m, 2H), 7.76(d, J=1.9 Hz, 1H), 7.92-7.95 (m, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.48 (s,1H), 8.77-8.79 (m, 1H), 13.23 (br s, 1H). ¹³C NMR (D6-DMSO) δ 9.5, 21.8,27.6, 36.6, 108.6, 110.6, 124.1, 125.4, 126.3, 126.7, 127.5, 128.0,128.4, 134.1, 136.7, 157.4, 169.2, 194.9. LCMS t=4.3 min, Calcd forC₁₈H₁₈NO₃; C₁₈H₁₇NNaO₃; C₃₆H₃₄N₂NaO₆ 296.13; 318.11; 613.23 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 296.15; 318.11; 613.17.

3-Amino-1-naphthoic acid: mp=179-181° C. ¹H NMR (D6-DMSO) δ 5.57 (br s,2H), 7.02 (d, J=2.1 Hz, 1H), 7.18-7.22 (m, 1H), 7.31-7.35 (m, 1H), 7.59(d, J=8.1 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 8.57 (d, J=8.5 Hz, 1H), 12.91(br s, 1H). ¹³C NMR (D6-DMSO) δ 110.6, 122.0, 122.4, 124.0, 125.4,125.9, 126.0, 128.4, 135.6, 145.5, 168.8. LCMS t=3.1 min, Calcd forC₁₁H₁₀NO₂; C₁₁H₉NNaO₂ 188.07; 210.05 [M+H]⁺; [M+Na]⁺, Found 188.16;210.13.

Example 01-53 Preparation of5-chloro-6-[(2-methyl-3-oxocyclohex-1-en-1-yl)amino]naphthalene-2-carboxylicacid (01-53)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and6-amino-5-chloro-2-naphthoic acid according to the procedure of Example01-01; 0.54 mmol scale refluxed for 48 h yielded 17 mg of greymicroneedles after recrystallization from EtOH (mp=272-275° C. decomp,10% yield). ¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.78-1.83 (m, 2H),2.23-2.26 (m, 2H), 2.37-2.40 (m, 2H), 7.49 (d, J=8.8 Hz, 1H), 8.12-8.15(m, 2H), 8.24-8.27 (m, 2H), 8.66 (d, J=1.5 Hz, 1H), 13.21 (s, 1H). ¹³CNMR (D6-DMSO) δ 9.6, 21.1, 27.8, 36.6, 109.4, 124.0, 124.1, 126.4,127.3, 128.1, 128.9, 130.7, 130.9, 132.7, 137.7, 157.6, 167.0, 195.3.LCMS t=4.8 min, m/z Calcd for C₁₈H₁₇ClNO₃; C₁₈H₁₆ClNNaO₃;C₃₆H₃₂Cl₂N₂NaO₆ 330.09; 352.07; 681.15 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found330.08; 352.06, 681.14.

6-Amino-5-chloro-2-naphthoic acid: 6-Amino-2-naphthoic acid (0.17 g, 0.9mmol), N-chlorosuccinimide (0.12 g, 1 eq), and carbon tetrachloride (25mL) were combined in a round bottom flask, and heated under reflux for 1h. After cooling to rt, the solid was filtered. The subsequent crudematerials were added directly to KP-Sil™ columns (10 g) with productsseparating from impurities using an isocratic solvent system CH₂Cl₂:MeOH(1:19), on the Biotage®-Isolera Four instrument, monitoring UV Trace at254/365 nm. The 0.9 mmol scale yielded 120 mg of white microcrystalsafter chromatography (mp=274-276° C. decomp, 60% yield). ¹H NMR(D6-DMSO) δ 6.14 (s, 2H), 7.19 (d, J=8.8 Hz, 1H), 7.85 (dd, J=42.2, 8.8Hz, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.96 (d, J=1.7 Hz, 1H), 8.39 (d, J=1.7Hz, 1H), 12.78 (s, 1H). ¹³C NMR (D6-DMSO) 107.5, 118.9, 121.1, 123.5,125.8, 126.9, 129.3, 130.9, 133.8, 145.0, 167.5. LCMS t=4.2 min, Calcdfor C₁₁H₉ClNO₂; C₁₁H₈ClNNaO₂ 222.03; 244.01 [M+H]+; [M+Na]+, Found222.09; 244.06.

Example 01-# TITLE COMPOUND NAME Q R T X Y Z 54 2-Methyl-3-[(quinolin-6-CH CH N CH CH CH yl)amino]cyclohex-2-en-1-one 553-[(Isoquinolin-6-yl)amino]-2- CH CH CH N CH CHmethylcyclohex-2-en-1-one 56 3-[(Isoquinolin-7-yl)amino]-2- CH CH CH CHN CH methylcyclohex-2-en-1-one 57 2-Methyl-3-[(quinolin-7- CH CH CH CHCH N yl)amino]cyclohex-2-en-1-one 58 3-[(isoquinolin-3-yl)amino]-2- N CHCH CH CH CH methylcyclohex-2-en-1-one 59 2-Methyl-3-[(quinolin-3- CH NCH CH CH CH yl)amino]cyclohex-2-en-1-one 60 2-Methyl-3-[(quinoxalin-6-CH CH N CH CH N yl)amino]cyclohex-2-en-1-one 612-Methyl-3-[(quinazolin-6- CH CH N CH N CH yl)amino]cyclohex-2-en-1-one

Example 01-54 Preparation of2-methyl-3-[(quinolin-6-yl)amino]cyclohex-2-en-1-one (01-54)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andquinolin-6-amine according to the procedure of Example 01-01 (brownmicrocrystals, mp=208-210° C.). ¹H NMR (D6-DMSO) δ 1.71 (s, 3H),1.77-1.88 (m, 2H), 2.26 (t, J=6.7 Hz, 2H), 2.58 (t, J=5.5 Hz, 2H),7.46-7.52 (m, 1H), 7.54-7.62 (m, 2H), 7.96 (d, J=9.8 Hz, 1H), 8.28 (d,J=7.3 Hz, 1H), 8.48 (s, 1H), 8.80 (d, J=6.1 Hz, 1H). ¹³C NMR (D6-DMSO) δ9.6, 21.8, 27.7, 36.6, 108.7, 119.2, 121.8, 127.2, 128.2, 129.4, 135.2,138.1, 144.8, 149.2, 157.5, 194.9. LCMS t=3.6 min, m/z Calcd forC₁₆H₁₇N₂O; C₁₆H₁₆N₂NaO; C₃₂H₃₂N₄NaO₂ 253.134; 275.116; 527.242 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 253.131; 275.112; 527.231.

Example 01-55 Preparation of3-[(isoquinolin-6-yl)amino]-2-methylcyclohex-2-en-1-one (01-55)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andisoquinolin-6-amine according to the procedure of Example 01-01 (brownmicrocrystals, mp=163-165° C.). ¹H NMR (D6-DMSO) δ 1.67 (s, 3H),1.81-1.89 (m, 2H), 2.29 (t, J=6.1 Hz, 2H), 2.63 (t, J=6.1 Hz, 2H), 7.40(s, 1H), 7.45 (dd, J=8.5, 2.4 Hz, 1H), 7.70 (d, J=4.9 Hz, 1H), 8.03 (d,J=8.5 Hz, 1H), 8.40 (d, J=4.9 Hz, 1H), 8.58 (s, 1H), 9.17 (s, 1H). ¹³CNMR (D6-DMSO) δ 10.1, 21.7, 28.1, 36.7, 111.0, 115.2, 119.6, 124.1,124.6, 128.4, 136.1, 142.1, 143.3, 156.5, 195.6. LCMS t=2.9 min, m/zCalcd for C₁₆H₁₇N₂O; C₁₆H₁₆N₂NaO 253.134; 275.116; [M+H]⁺; [M+Na]⁺,Found 253.129; 275.112.

Example 01-56 Preparation of3-[(isoquinolin-7-yl)amino]-2-methylcyclohex-2-en-1-one (01-56)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andisoquinolin-7-amine according to the procedure of Example 01-01 (yellowmicrocrystals, mp=145-147° C.). ¹H NMR (D6-DMSO) δ 1.70 (s, 3H), 1.84(quin, J=6.1 Hz, 2H), 2.27 (t, J=6.1 Hz, 2H), 2.59 (t, J=6.1 Hz, 2H),7.61 (dd, J=8.5, 2.4 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.80 (d, J=6.1 Hz,1H), 7.94 (d, J=8.5 Hz, 1H), 8.42 (d, J=6.1 Hz, 1H), 8.54 (s, 1H), 9.25(s, 1H). ¹³C NMR (D6-DMSO) δ 9.7, 21.7, 27.7, 36.6, 109.2, 118.3, 120.3,127.2, 128.4, 128.7, 131.9, 139.2, 141.3, 151.2, 157.2, 195.1. LCMSt=2.8 min, m/z Calcd for C₁₆H₁₇N₂O; C₁₆H₁₆N₂NaO; C₃₂H₃₂N₄NaO₂ 253.134;275.116; 527.242 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 253.128; 275.108;527.227.

Example 01-57 Preparation of2-methyl-3-[(quinolin-7-yl)amino]cyclohex-2-en-1-one (01-57)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andquinolin-7-amine according to the procedure of Example 01-01 (yellowmicrocrystals, mp=133-135° C.). ¹H NMR (D6-DMSO) δ 1.70 (s, 3H), 1.84(quin, J=6.1 Hz, 2H), 2.28 (t, J=6.7 Hz, 2H), 2.62 (t, J=5.5 Hz, 2H),7.39-7.45 (m, 2H), 7.54 (d, J=2.4 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 8.29(d, J=6.1 Hz, 1H), 8.53 (s, 1H), 8.82-8.85 (m, 1H). ¹³C NMR (D6-DMSO) δ9.8, 21.8, 27.9, 36.6, 109.7, 119.2, 120.1, 123.8, 124.3, 128.4, 135.6,141.3, 148.3, 151.0, 157.1, 195.3. LCMS t=3.4 min, m/z Calcd forC₁₆H₁₇N₂O; C₁₆H₁₆N₂NaO; C₃₂H₃₂N₄NaO₂ 253.134; 275.116; 527.242 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 253.127; 275.109; 527.228.

Example 01-58 Preparation of3-[(isoquinolin-3-yl)amino]-2-methylcyclohex-2-en-1-one (01-58)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andisoquinolin-3-amine according to the procedure of Example 01-01 (greymicroneedles, mp=205-208° C.). ¹H NMR (D6-DMSO) δ 1.72 (s, 3H), 1.84(quin, J=6.1 Hz, 2H), 2.27 (t, J=6.7 Hz, 2H), 2.80 (t, J=5.5 Hz, 2H),7.41 (s, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.65-7.73 (m, 1H), 7.84 (d, J=8.5Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 8.20-8.20 (m, 1H), 8.70 (s, 1H), 9.12(s, 1H). ¹³C NMR (D6-DMSO) δ 9.5, 21.8, 28.1, 36.7, 108.7, 110.2, 125.0,125.4, 125.7, 127.7, 130.9, 137.3, 148.9, 151.1, 157.0, 195.4. LCMSt=4.8 min, m/z Calcd for C₁₆H₁₇N₂O; C₁₆H₁₆N₂NaO; C₃₂H₃₂N₄NaO₂ 253.134;275.116; 527.242 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 253.131; 275.108;527.227.

Example 01-59 Preparation of2-methyl-3-[(quinolin-3-yl)amino]cyclohex-2-en-1-one (01-59)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andquinolin-3-amine according to the procedure of Example 01-01 (tanmicrocrystals, mp=172-175° C.). ¹H NMR (D6-DMSO) δ 1.73 (s, 3H), 1.83(quin, J=6.1 Hz, 2H), 2.26 (t, J=6.1 Hz, 2H), 2.58 (t, J=6.1 Hz, 2H),7.57-7.61 (m, 1H), 7.64-7.69 (m, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.95-8.01(m, 2H), 8.51 (s, 1H), 8.78 (d, J=2.4 Hz, 1H). ¹³C NMR (D6-DMSO) δ 9.4,21.7, 27.2, 36.5, 108.8, 126.4, 127.1, 127.5, 127.7, 128.1, 128.6,133.8, 144.2, 148.3, 157.4, 194.9. LCMS t=4.5 min, m/z Calcd forC₁₆H₁₇N₂O; C₁₆H₁₆N₂NaO; C₃₂H₃₂N₄NaO₂ 253.134; 275.116; 527.242 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 253.130; 275.106; 527.227.

Example 01-60 Preparation of2-methyl-3-[(quinoxalin-6-yl)amino]cyclohex-2-en-1-one (01-60)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andquinolin-6-amine according to the procedure of Example 01-01 (yellowmicrocrystals, mp=110-112° C.). ¹H NMR (D6-DMSO) δ 1.69 (s, 3H),1.83-1.90 (m, 2H), 2.30 (t, J=6.7 Hz, 2H), 2.63-2.70 (m, 2H), 7.52 (d,J=2.4 Hz, 1H), 7.66 (dd, J=8.5, 2.4 Hz, 1H), 8.01 (d, J=9.8 Hz, 1H),8.66 (s, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.86 (s, 1H). ¹³C NMR (D6-DMSO) δ10.1, 21.7, 28.0, 36.7, 111.3, 117.4, 126.8, 129.4, 138.9, 142.0, 143.0,143.6, 145.9, 156.4, 195.7. LCMS t=4.2 min, m/z Calcd for C₁₅H₁₆N₃O;C₁₅H₅N₃NaO; C₃₀H₃₁N₆NaO₂ 254.129; 276.111; 529.233 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 254.121; 276.102; 529.219.

Example 01-61 Preparation of2-methyl-3-[(quinazolin-6-yl)amino]cyclohex-2-en-1-one (01-61)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andquinazolin-6-amine according to the procedure of Example 01-01 (tanmicrocrystals, mp=215-216° C.). ¹H NMR (D6-DMSO) δ 1.69 (s, 3H),1.83-1.88 (m, 2H), 2.29 (t, J=6.1 Hz, 2H), 2.61-2.64 (m, 2H), 7.63 (d,J=2.4 Hz, 1H), 7.79-7.85 (m, 1H), 7.96 (d, J=8.5 Hz, 1H), 8.61 (s, 1H),9.18 (s, 1H), 9.51 (s, 1H). ¹³C NMR (D6-DMSO) δ ppm 10.0, 21.7, 27.8,36.7, 110.4, 116.7, 125.2, 128.3, 131.5, 139.7, 146.0, 153.7, 156.6,159.5, 195.4. LCMS t=3.8 min, m/z Calcd for C₁₅H₁₆N₃O; C₁₅H₁₅N₃NaO;C₃₀H₃₁N₆NaO₂ 254.129; 276.111; 529.233 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found254.120; 276.102; 529.218.

Example 01-62 Preparation of3-[(1H-indol-6-yl)amino]-2-methylcyclohex-2-en-1-one (01-62)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and1H-indol-6-amine according to the procedure of Example 01-01 (whitemicroneedles, mp=227-230° C.). ¹H NMR (D6-DMSO) δ 1.71 (s, 3H),1.72-1.77 (m, 2H), 2.17 (t, J=6.7 Hz, 2H), 2.36-2.40 (m, 2H), 6.41 (brs, 1H), 6.79-6.83 (m, 1H), 7.15 (s, 1H), 7.33 (t, J=2.4 Hz, 1H), 7.49(d, J=8.5 Hz, 1H), 8.20 (s, 1H), 11.09 (br s, 1H). ¹³C NMR (D6-DMSO) δ8.9, 21.7, 27.2, 36.4, 101.0, 104.9, 108.5, 118.1, 119.8, 125.3, 125.8,133.3, 135.8, 159.7, 193.6. LCMS t=4.6 min, m/z Calcd for C₁₅H₁₇N₂O;C₁₅H₁₆N₂NaO; C₃₀H₃₂N₄NaO₂ 241.134; 263.116; 503.242 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 241.141; 263.106; 503.224.

Example 01-63 Preparation of5-[(2-methyl-3-oxocyclohex-1-en-1-yl)amino]-2,3-dihydro-1H-1,3-benzodiazol-2-one(01-63)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and5-amino-1H-benzo[d]imidazol-2(3H)-one according to the procedure ofExample 01-01 (brown microcrystals, mp=233-235° C.). ¹H NMR (D6-DMSO) δ1.67 (s, 3H), 1.70-1.77 (m, 2H), 2.16 (t, J=6.1 Hz, 2H), 2.29-2.36 (m,2H), 6.71 (s, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 8.08(s, 1H), 10.63 (d, J=13.4 Hz, 2H). ¹³C NMR (D6-DMSO) δ 8.8, 21.6, 27.0,36.4, 105.1, 106.6, 108.2, 118.5, 127.2, 129.9, 132.7, 155.5, 159.4,193.7. LCMS t=3.2 min, m/z Calcd for C₁₄H₁₆N₃O₂; C₁₄H₁₅N₃NaO₂;C₂₈H₃₀N₆NaO₄ 258.124; 280.106; 537.222 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found258.123; 280.096; 537.206.

Example 01-64 Preparation of5-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-1H-indole-2-carboxylic acid(01-64)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and5-amino-1H-indole-2-carboxylic acid according to the procedure ofExample 01-01 (brown microcrystals, mp=310-315° C.). ¹H NMR (D6-DMSO) δ1.69-1.77 (m, 5H), 2.17 (t, J=6.3 Hz, 2H), 2.32-2.37 (m, 2H), 6.98-7.17(m, 2H), 7.33-7.50 (m, 2H), 8.21 (s, 1H), 11.84 (s, 1H), 13.05 (br s,1H). ¹³C NMR (D6-DMSO) δ 8.8, 21.6, 27.1, 36.4, 104.8, 107.3, 112.6,118.6, 124.0, 126.9, 129.4, 132.2, 135.2, 159.8, 162.7, 193.7. LCMSt=3.8 min, m/z Calcd for C₁₆H₁₇N₂O₃; C₃₂H₃₃N₄O₆; C₃₂H₃₂N₄NaO₆ 285.124;569.240; 591.221 [M+H]⁺; [2M+H]⁺; [2M+Na]⁺, Found 285.123; 569.239;591.220.

Examples 02-01 to 02-07

EXAM- PLE TITLE COMPOUND 02-# NAME R¹ R² R³ 014-((2-Methyl-3-oxocyclopent-1- H H CO₂H en-1-yl)amino)benzoic acid 023-Chloro-4-((2-methyl-3- Cl H CO₂H oxocyclopent-1-en-1- yl)amino)benzoicacid 03 2-Methoxy-4-((2-methyl-3- H OCH₃ CO₂H oxocyclopent-1-en-1-yl)amino)benzoic acid 04 2-((2-Methyl-3-oxocyclopent-1- CO₂H H Hen-1-yl)amino)benzoic acid 05 5-Chloro-2-((2-methyl-3- CO₂H H Cloxocyclopent-1-en-1- yl)amino)benzoic acid 06 3-Fluoro-4-((2-methyl-3- FH CO₂H oxocyclopent-1-en-1- yl)amino)benzoic acid 073-Bromo-4-((2-methyl-3- Br H CO₂H oxocyclopent-1-en-1- yl)amino)benzoicacid

Example 02-01 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-01)

Example 01-01 (1.0 g, 4.1 mmol) was stirred in a THF:H₂O (70 mL, 2:1)solution with sodium hydroxide (0.8 g, ˜5 eq), for 18 h. Aqueoushydrochloric acid was added until pH paper read at, or below, 3.Additional THF was added forming one layer and precipitating thehydrolyzed product, which was collected by filtration. The reaction on a4.1 mmol scale yielded 0.36 g of the title compound, yellow microneedles(mp=228-230° C., 43% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26 (s,2H), 2.80 (s, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 9.19(s, 1H). LCMS t=4.7 min, m/z Calcd for C₁₃H₁₄NO₃; C₁₃H₁₃NNaO₃;C₂₆H₂₇N₂O₆; C₂₆H₂₆N₂NaO₆ 232.10; 254.08; 463.19; 485.17 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 232.11; 254.09; 463.21; 485.19.

Example 02-02 Preparation of3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(02-02)

The title compound was prepared from Example 01-11 according to theprocedure of Example 02-01; 6.0 mmol scale yielded 1.2 g of yellowmicrocrystals (mp=226-230° C., 86% yield). ¹H NMR (D6-DMSO) δ 1.45 (s,3H), 2.23-2.25 (m, 2H), 2.52-2.54 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.88(d, J=8.2 Hz, 1H), 7.99 (s, 1H), 8.97 (s, 1H), 13.21 (br s, 1H). LCMSt=5.2 min, m/z Calcd for C₁₃H₁₃ClNO₃; C₁₃H₁₂ClNNaO₃; C₂₆H₂₄Cl₂N₂NaO₆266.06; 288.04; 553.09 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 266.11; 288.09;553.08.

Example 02-03 Preparation of2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(02-03)

The title compound was prepared from Example 01-13 according to theprocedure of Example 02-01; 18.0 mmol scale yielded 3.6 g of yellowmicrocrystals (mp=240-243° C., 87% yield). ¹H NMR (D6-DMSO) δ 1.62 (s,3H), 2.25-2.27 (m, 2H), 2.82-2.84 (m, 2H), 3.85 (s, 3H), 6.86 (d, J=8.4Hz, 1H), 6.95 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 9.16 (s, 1H). LCMS t=4.9min, m/z Calcd for C₁₄H₁₆NO₄; C₁₄H₁₅NNaO₄; C₂₈H₃₀N₂NaO₈ 262.11; 284.09;545.19 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 262.17; 284.14; 545.20.

Example 02-04 Preparation of2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-04)

The title compound was prepared from Example 01-19 according to theprocedure of Example 02-01; 13.7 mmol scale yielded 3.0 g of yellowmicrocrystals (mp=245-248° C., 95% yield). ¹H NMR (D6-DMSO) δ 1.62 (s,3H), 2.30-2.32 (m, 2H), 2.96-2.98 (m, 2H), 7.11 (t, J=7.5 Hz, 1H), 7.53(d, J=8.3 Hz, 1H), 7.56-7.60 (m, 1H), 7.99 (d, J=7.9 Hz, 1H), 10.68 (s,1H). ¹³C NMR (D6-DMSO) δ 6.6, 26.6, 33.3, 113.1, 117.2, 119.3, 121.8,131.8, 134.2, 142.4, 167.9, 169.8, 201.8. LCMS t=4.7 min, m/z Calcd forC₁₃H₁₄NO₃; C₁₃H₁₃NNaO₃; C₂₆H₂₇N₂O₆; C₂₆H₂₆N₂NaO₆ 232.10; 254.08; 463.19;485.17 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 232.10; 254.08; 463.19;485.17.

Example 02-05 Preparation of5-chloro-2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(02-05)

The title compound was prepared from Example 01-20 according to theprocedure of Example 02-01; 2.5 mmol scale yielded 0.54 g of yellowmicrocrystals (mp=242-245° C., 81% yield). ¹H NMR (D6-DMSO) δ 1.62 (s,3H), 2.32-2.34 (m, 2H), 2.93-2.95 (m, 2H), 7.55 (d, J=8.9 Hz, 1H), 7.62(dd, J=8.9, 2.6 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H), 10.60 (s, 1H). LCMSt=5.1 min, m/z Calcd for C₁₃H₁₃ClNO₃; C₁₃H₁₂ClNNaO₃; C₂₆H₂₅Cl₂N₂O₆;C₂₆H₂₄Cl₂N₂NaO₆ 266.06; 288.04; 531.11; 553.09 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 266.06; 288.04; 531.10; 553.09.

Example 02-06 Preparation of3-fluoro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid(02-06)

The title compound was prepared from Example 01-21 according to theprocedure of Example 02-01; 15.0 mmol scale yielded 2.9 g of yellowmicrocrystals (mp=210-213° C., 77% yield). ¹H NMR (D6-DMSO) δ 1.52 (s,3H), 2.23-2.25 (m, 2H), 2.54-2.56 (m, 2H), 7.41 (d, J=8.3 Hz, 1H),7.73-7.78 (m, 2H), 9.07 (s, 1H). LCMS t=4.4 min, m/z Calcd forC₁₃H₁₃FNO₃; C₁₃H₁₂FNNaO₃; C₂₆H₂₅F₂N₂O₆; C₂₆H₂₄F₂N₂NaO₆ 250.09; 272.07;499.17; 521.15 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 250.09; 272.07;499.17; 521.15.

Example 02-07 Preparation of3-bromo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-07)

The title compound was prepared from Example 01-22 according to theprocedure of Example 02-01; 9.5 mmol scale yielded 1.7 g of yellowmicrocrystals (mp=246-248° C., 58% yield). ¹H NMR (D6-DMSO) δ 1.47 (s,3H), 2.26-2.28 (m, 2H), 2.50-2.52 (m, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.94(dd, J=8.2, 1.8 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 9.13 (s, 1H). ¹³C NMR(D6-DMSO) δ 7.63, 25.9, 32.5, 110.9, 119.4, 127.3, 129.3, 133.6, 141.9,165.6, 169.7, 202.5. LCMS t=4.6 min, m/z Calcd for C₁₃H₁₃BrNO₃;C₁₃H₁₂BrNNaO₃; C₂₆H₂₅Br₂N₂O₆; C₂₆H₂₄Br₂N₂NaO₆ 310.01, 312.01; 331.99,333.99; 621.01; 642.99 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 310.01,312.01; 331.99, 333.99; 621.00; 642.99.

Example 02-08 Preparation of3-iodo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-08)

The title compound was prepared from Example 01-43 according to theprocedure of Example 02-01; 5.5 mmol scale yielded 1.7 g of yellowprecipitate (87% yield), pale yellow microcrystals from EtOH(mp=263-264° C.). ¹H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.20-2.23 (m, 2H),2.42-2.44 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.94 (dd, J=8.2, 1.7 Hz, 1H),8.38 (d, J=1.7 Hz, 1H), 8.86 (s, 1H), 13.22 (s, 1H). ¹³C NMR (D6-DMSO) δ7.6, 25.8, 32.7, 97.9, 110.2, 126.9, 129.5, 129.9, 139.8, 145.3, 165.5,168.7, 202.5. LCMS t=4.4 min, m/z Calcd for C₁₃H₁₃INO₃; C₁₃H₁₂INNaO₃;C₂₆H₂₄I₂N₂NaO₆ 357.994; 379.976; 736.962 [M+H]+; [M+Na]+; [2M+Na]+,Found 357.995; 379.965; 736.944.

Example 02-09 Preparation of methyl4-bromo-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoate (02-09)

Acetyl chloride (14 eq) was added to a CH₂Cl₂:MeOH (60 mL, 1:2) mixtureat 0° C., followed by Example 01-48 (1.6 g, 5.0 mmol). After warming tort, the mixture was stirred overnight. The solvent was removed on therotovap to provide the crude material. 5.0 mmol scale yielded 1.23 g ofbrown microcrystals slowly from EtOAc (mp=211-213° C., 76% yield). ¹HNMR (D6-DMSO) δ 1.74 (s, 3H), 1.78-1.81 (m, 2H), 2.25-2.29 (m, 2H),2.38-2.41 (m, 2H), 3.88 (s, 3H), 7.81 (dd, J=8.4, 2.0 Hz, 1H), 7.87 (d,J=2.0 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 9.30 (s, 1H). ¹³C NMR (D6-DMSO) δ8.9, 20.7, 27.2, 34.0, 52.6, 106.8, 127.2, 128.9, 129.3, 130.0, 133.7,138.2, 165.1, 192.3. LCMS t=5.0 min, m/z Calcd for C₁₅H₁₇BrNO₃;C₁₅H₁₆BrNNaO₃; C₃₀H₃₃Br₂N₂NaO₆ 338.04, 340.04; 360.02, 362.02; 699.05[M+H]+; [M+Na]+; [2M+Na]+, Found 324.03, 326.02; 345.99, 347.99; 670.96.

EXAM- PLE TITLE COMPOUND 02-# NAME R¹ R² R³ 10 3-((5-Amino-2- H H NH₂chlorophenyl)amino)-2- methylcyclohex-2-enone 11 3-((3-Amino-2- NH₂ H Hchlorophenyl)amino)-2- methylcyclohex-2-enone 12 3-((4-Amino-2- H NH₂ Hchlorophenyl)amino)-2- methylcyclohex-2-enone

Example 02-10 Preparation of3-((5-amino-2-chlorophenyl)amino)-2-methylcyclohex-2-enone (02-10)

3-((2-Chloro-5-nitrophenyl)amino)-2-methylcyclohex-2-enone (2 g, 7mmol), Fe (1.6 g, 28 mmol), and NH₄Cl (0.76 g, 14 mmol) were stirred inTHF:EtOH:H₂O (48 mL, 1:1:0.4) at 90° C., for 2 h. The mixture wasfiltered. The filtrate was diluted with EtOAc (50 mL), washed with brine(2×30 mL), dried with Na₂SO₄, and filtered. The second filtrate wasconcentrated to provide the title compound (1.5 g, 84% yield,mp=182-184° C.). ¹H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.71-1.82 (m, 2H),2.15 (t, J=6.1 Hz, 2H), 2.18-2.22 (m, 2H), 5.37 (s, 2H), 6.45 (d, J=2.4Hz, 1H), 6.47 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.84 (s,1H). ¹³C NMR (D6-DMSO) δ 8.8, 21.2, 26.7, 36.4, 105.8, 113.2. 114.1,116.6, 129.6, 137.0, 148.5, 159.2, 194.1. LCMS t=3.8 min, m/z Calcd forC₁₃H₁₆ClN₂O; C₁₃H₁₅ClN₂NaO; C₂₆H₃₀Cl₂N₄NaO₂ 251.095; 273.077; 523.164[M+H]+; [M+Na]+; [2M+Na]+, Found 251.095; 273.076; 523.163.

3-((2-Chloro-5-nitrophenyl)amino)-2-methylcyclohex-2-enone (5.6 g ofyellow solid, 50% yield) was prepared from 2-methyl-1,3-cyclohexandione(40 mmol) and 2-chloro-5-nitroaniline according to the procedure ofExample 01-01.

Example 02-11 Preparation of3-((3-amino-2-chlorophenyl)amino)-2-methylcyclohex-2-enone (02-11)

The title compound was prepared from3-((2-chloro-3-nitrophenyl)amino)-2-methylcyclohex-2-enone according tothe procedure of Example 02-10. ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.73(quin, J=6.1 Hz, 2H), 2.15 (t, J=6.1 Hz, 2H), 2.19 (t, J=6.1 Hz, 2H),5.49 (br s, 2H), 6.47 (d, J=7.3 Hz, 1H), 6.70 (d, J=9.8 Hz, 1H), 7.01(t, J=7.9 Hz, 1H), 7.87 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.7, 21.3, 26.6,36.3, 105.7, 105.7, 113.0, 115.3, 116.1, 126.9, 137.3, 145.8, 159.4,194.0. LCMS t=4.0 min, m/z Calcd for C₁₃H₁₆ClN₂O; C₁₃H₁₅ClN₂NaO;C₂₆H₃₀Cl₂N₄NaO₂ 251.095; 273.077; 523.164 [M+H]+; [M+Na]+; [2M+Na]+,Found 251.095; 273.076; 523.163.

3-((2-Chloro-3-nitrophenyl)amino)-2-methylcyclohex-2-enone was preparedfrom 2-methyl-1,3-cyclohexandione and 2-chloro-3-nitroaniline accordingto the procedure of Example 01-01.

Example 02-12 Preparation of3-((4-amino-2-chlorophenyl)amino)-2-methylcyclohex-2-enone (02-12)

The title compound was prepared from3-((2-chloro-4-nitrophenyl)amino)-2-methylcyclohex-2-enone according tothe procedure of Example 02-10 (mp=156-158° C.). ¹H NMR (D6-DMSO) δ 1.66(s, 3H), 1.71 (quin, J=6.1 Hz, 2H), 2.07 (t, J=5.5 Hz, 2H), 2.12 (t,J=6.1 Hz, 2H), 5.47 (s, 2H), 6.51 (dd, J=8.5, 2.4 Hz, 1H), 6.68 (d,J=2.4 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 7.77 (s, 1H). ¹³C NMR (D6-DMSO) δ8.4, 21.2, 26.2, 36.2, 104.2, 112.8, 113.4, 124.2, 130.9, 132.6, 149.0,160.8, 193.5. LCMS t=3.7 min, m/z Calcd for C₁₃H₁₆ClN₂O; C₁₃H₁₅ClN₂NaO;C₂₆H₃₀Cl₂N₄NaO₂ 251.095; 273.077; 523.164 [M+H]+; [M+Na]+; [2M+Na]+,Found 251.095; 273.077; 523.164.

3-((2-Chloro-4-nitrophenyl)amino)-2-methylcyclohex-2-enone was preparedfrom 2-methyl-1,3-cyclohexandione and 2-chloro-4-nitroaniline accordingto the procedure of Example 01-01.

EXAM- PLE TITLE COMPOUND 02-# NAME R¹ R² R³ 13 3-((3-Amino-2- NH₂ H Hchlorophenyl)amino)-2- methylcyclopent-2-enone 14 3-((4-Amino-2- H NH₂ Hchlorophenyl)amino)-2- methylcyclopent-2-enone 15 3-((5-Amino-2- H H NH₂chlorophenyl)amino)-2- methylcyclopent-2-en-1-one

Example 02-13 Preparation of3-((3-amino-2-chlorophenyl)amino)-2-methylcyclopent-2-enone (02-13)

The title compound was prepared from3-((2-chloro-3-nitrophenyl)amino)-2-methylcyclopent-2-enone according tothe procedure of Example 02-10 (mp=223-225° C.). ¹H NMR (D6-DMSO) δ 1.46(s, 3H), 2.12-2.17 (m, 2H), 2.32-2.39 (m, 2H), 5.49 (br s, 2H), 6.53 (d,J=7.3 Hz, 1H), 6.71 (d, J=6.1 Hz, 1H), 6.99-7.03 (m, 1H), 8.72 (s, 1H).¹³C NMR (D6-DMSO) δ 7.1, 25.3, 32.6, 108.2, 113.1, 114.6, 115.5, 127.0,136.9, 145.8, 170.3, 201.8. LCMS t=3.7 min, m/z Calcd for C₁₂H₁₄ClN₂O;C₁₂H₁₃ClN₂NaO; C₂₄H₂₇Cl₂N₄O₂; C₂₄H₂₆Cl₂N₄NaO₂ 237.080; 259.061; 473.151;495.133 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 237.080; 259.060;473.150 495.132.

3-((2-Chloro-3-nitrophenyl)amino)-2-methylcyclopent-2-enone was preparedfrom 2-methyl-1,3-cyclopentandione and 2-chloro-3-nitroaniline accordingto the procedure of Example 01-01.

Example 02-14 Preparation of3-((4-amino-2-chlorophenyl)amino)-2-methylcyclopent-2-enone (02-14)

The title compound was prepared from3-((2-chloro-4-nitrophenyl)amino)-2-methylcyclopent-2-enone according tothe procedure of Example 02-10. ¹H NMR (D6-DMSO) δ 1.44 (s, 3H),2.09-2.13 (m, 2H), 2.18-2.27 (m, 2H), 5.47 (br s, 2H), 6.50 (dd, J=8.5,2.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 8.58 (s,1H). ¹³C NMR (D6-DMSO) δ 6.9, 25.1, 32.5, 107.0, 112.7, 113.4, 123.9,130.4, 131.9, 149.0, 171.9, 201.4. LCMS t=3.5 min, m/z Calcd forC₁₂H₁₄ClN₂O; C₁₂H₁₃ClN₂NaO; C₂₄H₂₇Cl₂N₄O₂; C₂₄H₂₆Cl₂N₄NaO₂ 237.080;259.061; 473.151; 495.133 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found237.080; 259.061; 473.151 495.132.

3-((2-Chloro-4-nitrophenyl)amino)-2-methylcyclopent-2-enone was preparedfrom 2-methyl-1,3-cyclopentandione and 2-chloro-4-nitroaniline accordingto the procedure of Example 01-01.

Example 02-15 Preparation of3-((5-amino-2-chlorophenyl)amino)-2-methylcyclopent-2-en-1-one (02-15)

The title compound was prepared from3-((2-chloro-5-nitrophenyl)amino)-2-methylcyclopent-2-enone according tothe procedure of Example 02-10 (mp=166-168° C.). ¹H NMR (D6-DMSO) δ 1.45(s, 3H), 2.13-2.21 (m, 2H), 2.34-2.40 (m, 2H), 5.38 (s, 2H), 6.47 (dd,J=8.5, 2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 8.69(s, 1H). ¹³C NMR (D6-DMSO) δ 7.2, 25.4, 32.6, 108.4, 113.2, 113.4,115.8, 129.6, 136.5, 148.4, 170.1, 202.0. LCMS t=3.6 min, m/z Calcd forC₁₂H₁₄ClN₂O; C₁₂H₁₃ClN₂NaO; C₂₄H₂₆Cl₂N₄NaO₂ 237.080; 259.061; 495.133[M+H]+; [M+Na]+; [2M+Na]+, Found 237.080; 259.061; 495.133.

3-((2-Chloro-5-nitrophenyl)amino)-2-methylcyclopent-2-enone was preparedfrom 2-methyl-1,3-cyclopentandione and 2-chloro-5-nitroaniline accordingto the procedure of Example 01-01.

Examples 03-01 to 03-23

EXAMPLE 03-# TITLE COMPOUND NAME R¹ R² R³ R⁴ 014-((2-Methyl-3-oxocyclopent-1-en-1- H H H H yl)amino)-N-phenylbenzamide02 N-Methyl-4-((2-methyl-3-oxocyclopent-1- CH₃ H H Hen-1-yl)amino)-N-phenylbenzamide 03 N-(2-Fluorophenyl)-4-((2-methyl-3- HF H H oxocyclopent-1-en-1-yl)amino)benzamide 04N-(3-Fluorophenyl)-4-((2-methyl-3- H H F Hoxocyclopent-1-en-1-yl)amino)benzamide 05N-(4-Chlorophenyl)-4-((2-methyl-3- H H H Cloxocyclopent-1-en-1-yl)amino)benzamide 06N-(4-Methoxyphenyl)-4-((2-methyl-3- H H H OCH₃oxocyclopent-1-en-1-yl)amino)benzamide 074-((2-Methyl-3-oxocyclopent-1-en-1- H H H CH₃yl)amino)-N-(p-tolyl)benzamide 08 4-((2-Methyl-3-oxocyclopent-1-en-1- HCH₃ H H yl)amino)-N-(o-tolyl)benzamide 094-((2-Methyl-3-oxocyclopent-1-en-1- H H CH₃ Hyl)amino)-N-(m-tolyl)benzamide 10 N-(2-Methoxyphenyl)-4-((2-methyl-3- HOCH₃ H H oxocyclopent-1-en-1-yl)amino)benzamide 11N-(3-Methoxyphenyl)-4-((2-methyl-3- H H OCH₃ Hoxocyclopent-1-en-1-yl)amino)benzamide 124-((2-Methyl-3-oxocyclopent-1-en-1- H H CF₃ H yl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide 13N-(4-(tert-Butyl)phenyl)-4-((2-methyl-3- H H H C(CH₃)₃oxocyclopent-1-en-1-yl)amino)benzamide 14N-(3-Bromophenyl)-4-((2-methyl-3- H H Br Hoxocyclopent-1-en-1-yl)amino)benzamide 15N-(4-Bromophenyl)-4-((2-methyl-3- H H H Broxocyclopent-1-en-1-yl)amino)benzamide

Example 03-01 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (03-01)

Example 02-01 (150 mg, 0.65 mmol, 1.3 eq) was dissolved in THF:DMF(1.5:1.0, 7.5 mL) and added to aniline (0.046 mL, 0.5 mmol) and PS-CDI(1.0 g, loading=1.33 mmol/g) in a dry reaction vessel. The reactionvessel was sealed and shaken for 18 h at rt. Resin was filtered from thesolvent, washed with 1 vol of the reaction solvent, and THF (3×8 mL).Isolute™ HM-N was added to the crude solution and dried on the rotovap.The crude material absorbed to Isolute™ was packed into an empty samplet(1 g) and placed into the receiving KP-Sil™ column (10 g). Products wereseparated from impurities using an isocratic solvent system,EtOAc:acetone (17:3), on Biotage®-Isolera Four instrument, monitoring UVTrace at 254/365 nm. The reaction on a 0.5 mmol scale yielded 15 mg ofthe title compound (10% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H),2.25-2.27 (m, 2H), 2.80-2.81 (m, 2H), 7.09 (t, J=7.3 Hz, 1H), 7.33-7.37(m, 4H), 7.77 (d, J=7.7 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 9.18 (s, 1H),10.16 (s, 1H). LCMS t=5.4 min, m/z Calcd for C₁₉H₁₉N₂O₂; C₁₉H₈N₂NaO₂;C₃₈H₃₇N₄O₄; C₃₈H₃₆N₄NaO₄ 307.14; 329.13; 613.28; 635.26 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 307.16; 329.14; 613.31; 635.29.

Example 03-02 Preparation ofN-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide(03-02)

The title compound was prepared from Example 02-01 and N-methylanilineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 30mg (19% yield). ¹H NMR (MeOD) δ 1.59 (s, 3H), 2.35-2.37 (m, 2H),2.68-2.69 (m, 2H), 3.47 (s, 3H), 7.08 (d, J=8.2 Hz, 2H), 7.15 (d, J=7.6Hz, 2H), 7.19 (t, J=7.3 Hz, 1H), 7.26-7.31 (m, 4H). LCMS t=5.4 min, m/zCalcd for C₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂; C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16;343.14; 641.31; 663.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 321.17;343.16; 641.34; 663.32.

Example 03-03 Preparation ofN-(2-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-03)

The title compound was prepared from Example 02-01 and 2-fluoroanilineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 10mg (6% yield). ¹H NMR (CDCl₃) δ 1.60 (s, 3H), 2.76-2.78 (m, 2H),3.34-3.36 (m, 2H), 6.68 (s, 1H), 7.10-7.28 (m, 5H), 7.92 (d, J=8.2 Hz,2H), 8.04 (s, 1H), 8.45 (t, J=8.0 Hz, 1H). LCMS t=5.4 min, m/z Calcd forC₁₉H₁₈FN₂O₂; C₁₉H₁₇FN₂NaO₂; C₃₈H₃₅F₂N₄O₄; C₃₈H₃₄F₂N₄NaO₄ 325.14; 347.12;649.26; 671.24 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 325.15; 347.13;649.29; 671.27.

Example 03-04 Preparation ofN-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-04)

The title compound was prepared from Example 02-01 and 3-fluoroanilineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 18mg (11% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.28 (m, 2H),2.80-2.82 (m, 2H), 6.91-6.93 (m, 1H), 7.36-7.39 (m, 3H), 7.56 (d, J=8.1Hz, 1H), 7.76 (d, J=11.8 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 9.19 (s, 1H),10.34 (s, 1H). LCMS t=5.5 min, m/z Calcd for C₁₉H₁₈FN₂O₂; C₁₉H₁₇FN₂NaO₂;C₃₈H₃₅F₂N₄O₄; C₃₈H₃₄F₂N₄NaO₄ 325.14; 347.12; 649.26; 671.24 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 325.15; 347.13; 649.29; 671.28.

Example 03-05 Preparation ofN-(4-chlorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-05)

The title compound was prepared from Example 02-01 and 4-chloroanilineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 10mg (6% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.27 (m, 2H),2.80-2.81 (m, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.82(d, J=8.8 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 9.19 (s, 1H), 10.29 (s, 1H).LCMS t=5.7 min, m/z Calcd for C₁₉H₁₈ClN₂O₂; C₁₉H₁₇ClN₂NaO₂;C₃₈H₃₅Cl₂N₄O₄; C₃₈H₃₄Cl₂N₄NaO₄ 341.11; 363.09; 681.20; 703.19 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 341.12; 363.09; 681.23; 703.21.

Example 03-06 Preparation ofN-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-06)

The title compound was prepared from Example 02-01 and 4-aminoanisoleaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 12mg (7% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.27 (m, 2H),2.79-2.80 (m, 2H), 3.74 (s, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 9.17 (s, 1H),10.05 (s, 1H). LCMS t=5.2 min, m/z Calcd for C₂₀H₂₁N₂O₃; C₄₀H₄₁N₄O₆;C₄₀H₄₀N₄NaO₆ 337.16; 673.30; 695.28 [M+H]⁺; [2M+H]⁺; [2M+Na]⁺, Found337.17; 673.33; 695.31.

Example 03-07 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide(03-07)

The title compound was prepared from Example 02-01 and 4-aminotolueneaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 25mg (16% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.28 (m, 5H),2.79-2.81 (m, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.65(d, J=8.2 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 9.17 (s, 1H), 10.08 (s, 1H).LCMS t=5.5 min, m/z Calcd for C₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂; C₄₀H₄₁N₄O₄;C₄₀H₄₀N₄NaO₄ 321.16; 343.14; 641.31; 663.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 321.17; 343.16; 641.34; 663.32.

Example 03-08 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(03-08)

The title compound was prepared from Example 02-01 and o-toluidineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 1 mg(1% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.31 (s,3H), 2.80-2.82 (m, 2H), 6.91 (d, J=6.4 Hz, 1H), 7.22 (s, 1H), 7.36 (d,J=6.9 Hz, 2H), 7.56 (d, J=6.4 Hz, 1H), 7.62 (s, 1H), 7.94 (d, J=6.9 Hz,2H), 9.18 (s, 1H), 10.08 (s, 1H). LCMS t=5.7 min, m/z Calcd forC₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂; C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16; 343.14;641.31; 663.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 321.18; 343.16;641.29; 663.28.

Example 03-09 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide(03-09)

The title compound was prepared from Example 02-01 and m-toluidineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 13mg (8% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.23 (s, 3H), 2.24-2.26(m, 2H), 2.79-2.80 (m, 2H), 7.16 (t, J=7.3 Hz, 1H), 7.21 (t, J=7.3 Hz,1H), 7.27 (d, J=7.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.4 Hz,2H), 7.96 (d, J=8.4 Hz, 2H), 9.18 (s, 1H), 9.81 (s, 1H). LCMS t=5.5 min,m/z Calcd for C₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂; C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16;343.14; 641.31; 663.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 321.18;343.16; 641.29; 663.28.

Example 03-10 Preparation ofN-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-10)

The title compound was prepared from Example 02-01 and o-anisidineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 8 mg(5% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.27 (m, 2H),2.79-2.81 (m, 2H), 3.84 (s, 3H), 6.97 (t, J=7.2 Hz, 1H), 7.09 (d, J=7.9Hz, 1H), 7.17 (t, J=7.3 Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.77 (d, J=7.4Hz, 1H), 7.94 (d, J=7.9 Hz, 2H), 9.18 (s, 1H), 9.34 (s, 1H). LCMS t=5.7min, m/z Calcd for C₂₀H₂₁N₂O₃; C₂₀H₂₀N₂NaO₃; C₄₀H₄₀N₄NaO₆ 337.16;359.14; 695.28 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 337.17; 359.14; 695.27.

Example 03-11 Preparation ofN-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-11)

The title compound was prepared from Example 02-01 and m-anisidineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 4 mg(2% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H),2.80-2.82 (m, 2H), 3.75 (s, 3H), 6.67 (d, J=7.3 Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.47 (s, 1H), 7.94 (d, J=8.3 Hz, 2H),9.18 (s, 1H), 10.12 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₂₀H₂₁N₂O₃;C₂₀H₂₀N₂NaO₃; C₄₀H₄₀N₄NaO₆ 337.16; 359.14; 695.28 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 337.17; 359.14; 695.28.

Example 03-12 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide(03-12)

The title compound was prepared from Example 02-01 and3-(trifluoromethyl)aniline according to the procedure of Example 03-01;0.5 mmol scale yielded 3 mg (2% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H),2.26-2.28 (m, 2H), 2.81-2.83 (m, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.45 (d,J=7.2 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.97 (d, J=7.9 Hz, 2H), 8.05 (d,J=7.6 Hz, 1H), 8.26 (s, 1H), 9.21 (s, 1H), 10.47 (s, 1H). LCMS t=5.9min, m/z Calcd for C₂₀H₁₈F₃N₂O₂; C₂₀H₁₇F₃N₂NaO₂; C₄₀H₃₄F₆N₄NaO₆ 375.13;397.11; 771.24 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 375.13; 397.11; 771.24.

Example 03-13 Preparation ofN-(4-(tert-butyl)phenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(03-13)

The title compound was prepared from Example 02-01 and4-tert-butylaniline according to the procedure of Example 03-01; 0.5mmol scale yielded 4 mg (2% yield). ¹H NMR (D6-DMSO) δ 1.28 (s, 9H),1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.79-2.81 (m, 2H), 7.36 (d, J=8.0 Hz,4H), 7.68 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.1 Hz, 2H), 9.18 (s, 1H), 10.10(s, 1H). LCMS t=6.1 min, m/z Calcd for C₂₃H₂₇N₂O₂; C₂₃H₂₆N₂NaO₂;C₄₆H₅₃N₄O₄; C₄₆H₅₂N₄NaO₄ 363.21; 385.19; 725.41; 747.39 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 363.21; 385.19; 725.41; 747.39.

Example 03-14 Preparation ofN-(3-bromophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-14)

The title compound was prepared from Example 02-01 and 3-bromoanilineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 4 mg(2% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H),2.81-2.83 (m, 2H), 7.29-7.34 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.75 (d,J=7.9 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 8.11 (s, 1H), 9.20 (s, 1H), 10.31(s, 1H). LCMS t=5.9 min, m/z Calcd for C₁₉H₁₈BrN₂O₂; C₁₉H₁₇BrN₂NaO₂;C₃₈H₃₄BrN₄NaO₆ 385.06, 387.05; 407.04, 409.04; 793.08 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 385.05, 387.05; 407.03, 409.03; 793.09.

Example 03-15 Preparation ofN-(4-bromophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-15)

The title compound was prepared from Example 02-01 and 4-bromoanilineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 3 mg(2% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H),2.80-2.82 (m, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.76(d, J=8.6 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 9.19 (s, 1H), 10.28 (s, 1H).LCMS t=5.9 min, m/z Calcd for C₁₉H₁₈BrN₂O₂; C₁₉H₁₇BrN₂NaO₂;C₃₈H₃₄BrN₄NaO₆ 385.06, 387.05; 407.04, 409.04; 793.08 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 385.05, 387.05; 407.03, 409.03; 793.09.

Example 03-16 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide(03-16)

The title compound was prepared from Example 02-01 and1-aminonaphthalene according to the procedure of Example 03-01; 0.5 mmolscale yielded 11 mg (6% yield). ¹H NMR (D6-DMSO) δ 1.64 (s, 3H),2.27-2.29 (m, 2H), 2.82-2.84 (m, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.54-7.60(m, 4H), 7.81-7.87 (m, 2H), 7.98-8.00 (m, 2H), 8.08 (d, J=8.3 Hz, 2H),9.21 (s, 1H), 10.36 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₂₃H₂₁N₂O₂;C₂₃H₂₀N₂NaO₂; C₄₆H₄₁N₄O₄; C₄₆H₄₀N₄NaO₄ 357.16; 379.14; 713.31; 735.29[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 357.18; 379.18; 713.34;735.33.

Example 03-17 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(pyridin-2-yl)benzamide(03-17)

The title compound was prepared from Example 02-01 and 2-aminopyridineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 2 mg(1% yield). ¹H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H),2.81-2.82 (m, 2H), 7.16 (s, 1H), 7.34 (d, J=7.8 Hz, 2H), 7.83-7.84 (m,1H), 8.03 (d, J=7.7 Hz, 2H), 8.18 (d, J=8.0 Hz, 2H), 8.39 (s, 1H), 9.18(s, 1H), 10.68 (s, 1H). LCMS t=5.1 min, m/z Calcd for C₁₈H₁₈N₃O₂;C₁₈H₁₇N₃NaO₂; C₃₆H₃₄N₆NaO₄ 308.14; 330.12; 637.25 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 308.16; 330.13; 637.22.

Example 03-18 Preparation ofN-benzyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-18)

The title compound was prepared from Example 02-01 and benzylamineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 20mg (13% yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H),2.76-2.78 (m, 2H), 4.47 (d, J=5.7 Hz, 2H), 7.23-7.30 (m, 7H), 7.87 (d,J=8.2 Hz, 2H), 8.98 (s, 1H), 9.12 (s, 1H). LCMS t=5.3 min, m/z Calcd forC₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂; C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16; 343.14;641.31; 663.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 321.17; 343.16;641.24; 663.32.

Example 03-19 Preparation ofN-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-19)

The title compound was prepared from Example 02-01 and cyclohexylamineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 11mg (7% yield). ¹H NMR (MeOD) δ 1.21-1.25 (m, 2H), 1.34-1.42 (m, 4H),1.69 (s, 3H), 1.80-1.83 (m, 2H), 1.94-1.96 (m, 2H), 2.40-2.43 (m, 2H),2.82-2.83 (m, 2H), 3.85-3.86 (m, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.83 (d,J=8.5 Hz, 2H). LCMS t=5.4 min, m/z Calcd for C₁₉H₂₅N₂O₂; C₁₉H₂₄N₂NaO₂;C₃₈H₄₉N₄O₄; C₃₈H₄₈N₄NaO₄ 313.19; 335.17; 625.38; 647.38 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 313.21; 335.19; 625.40; 647.39.

Example 03-20 Preparation ofN,N-dimethyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(03-20)

The title compound was prepared from Example 02-01 and dimethylamineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 55mg (43% yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.21-2.23 (m, 2H),2.73-2.74 (m, 2H), 2.96 (s, 6H), 7.27 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3Hz, 2H), 9.07 (s, 1H). LCMS t=5.0 min, m/z Calcd for C₁₅H₁₉N₂O₂;C₁₅H₈N₂NaO₂; C₃₀H₃₇N₄O₄; C₃₀H₃₆N₄NaO₄ 259.14; 281.13; 517.28; 539.26[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 259.19; 281.16; 517.25;539.23.

Example 03-21 Preparation of2-methyl-3-((4-(piperidine-1-carbonyl)phenyl)amino)cyclopent-2-enone(03-21)

The title compound was prepared from Example 02-01 and piperidineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 33mg (22% yield). ¹H NMR (D6-DMSO) δ 1.50 (br s, 8H), 1.59 (s, 3H),2.22-2.24 (m, 2H), 2.72-2.24 (m, 2H), 3.53 (br s, 2H), 7.27 (d, J=8.0Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 9.06 (s, 1H). LCMS t=5.4 min, m/z Calcdfor C₁₈H₂₃N₂O₂; C₁₈H₂₂N₂NaO₂; C₃₆H₄₅N₄O₄; 299.18; 321.16; 619.33 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 299.20; 321.17; 619.29.

Example 03-22 Preparation of2-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino)cyclopent-2-enone(03-22)

The title compound was prepared from Example 02-01 and morpholineaccording to the procedure of Example 03-01; 0.5 mmol scale yielded 59mg (39% yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.22-2.24 (m, 2H),2.73-2.75 (m, 2H), 3.40-3.70 (m, 8H), 7.28 (d, J=8.1 Hz, 2H), 7.40 (d,J=8.1 Hz, 2H), 9.08 (s, 1H). LCMS t=4.9 min, m/z Calcd for C₁₇H₂₁N₂O₃;C₁₇H₂₀N₂NaO₃; C₃₄H₄₀N₄NaO₆ 301.16; 323.14; 623.28 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 301.18; 323.15; 623.25.

Example 03-23 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (03-23)

The title compound was prepared from Example 01-03 and aniline accordingto the procedure of Example 03-01; 0.5 mmol scale yielded 8 mg (5%yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.74(m, 2H), 7.11 (t, J=7.1 Hz, 1H), 7.36 (t, J=7.5 Hz, 2H), 7.46 (d, J=7.6Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.77 (d, J=7.8Hz, 2H), 7.79 (s, 1H), 9.15 (s, 1H), 10.26 (s, 1H). LCMS t=5.6 min, m/zCalcd for C₁₉H₁₉N₂O₂; C₁₉H₁₈N₂NaO₂; C₃₈H₃₇N₄O₄; C₃₈H₃₆N₄NaO₄ 307.14;329.13; 613.28; 635.26 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 307.17;329.15; 613.26; 635.24.

Examples 04-01 to 04-103

Example 04-01 Preparation ofN-cyclohexyl-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-01)

Method A; Isobutylchloroformate (IBCF, 0.285 mL, 2.0 eq) was added toExample 01-03 (250 mg, 1.1 mmol, 1.0 eq) stirring in CH₂Cl₂ (1.0 mL), ina screw-capped vial. N-Methylmorpholine (NMM, 0.36 mL, 3.0 eq) was addedat 0° C. in 3 portions. After stirring for 1 h, cyclohexylamine (0.15mL, 1.2 eq) was added, sealed, and stirred for 18 h at rt. Crudematerials were purified by recrystallization. The reaction on a 1.1 mmolscale yielded 140 mg of the title compound after recrystallization fromCHCl₃ (41% yield). ¹H NMR (D6-DMSO) δ 1.10-1.16 (m, 1H), 1.30-1.36 (m,4H), 1.57 (s, 3H), 1.61 (d, J=9.7 Hz, 1H), 1.73-1.74 (m, 2H), 1.80-1.82(m, 2H), 2.20-2.23 (m, 2H), 2.64-2.66 (m, 2H), 3.75-3.77 (m, 1H), 7.37(d, J=8.1 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.69(s, 1H), 8.22 (d, J=7.9 Hz, 1H), 9.08 (s, 1H). LCMS t=5.8 min, m/z Calcdfor C₁₉H₂₅N₂O₂; C₁₉H₂₄N₂NaO₂; C₃₈H₄₉N₄O₄; C₃₈H₄₉N₄NaO₄ 313.19; 335.17;625.38; 647.36 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 313.23; 335.20;625.37; 647.37.

Example 04-02 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide(04-02)

The title compound was prepared from Example 01-03 and1-aminonaphthalene according to the procedure of Example 04-01; 1.1 mmolscale yielded 100 mg after recrystallization from CHCl₃ (26% yield). ¹HNMR (D6-DMSO) δ 1.61 (s, 3H), 2.23-2.25 (m, 2H), 2.74-2.76 (m, 2H), 7.50(d, J=7.9 Hz, 2H), 7.53-7.58 (m, 4H), 7.60 (d, J=7.2 Hz, 2H), 7.87 (t,J=8.9 Hz, 2H), 7.91 (s, 1H), 7.96-8.00 (m, 2H), 9.17 (s, 1H), 10.46 (s,1H). LCMS t=5.9 min, m/z Calcd for C₂₃H₂₁N₂O₂; C₂₃H₂₀N₂NaO₂; C₄₆H₄₁N₄O₄;C₄₆H₄₀N₄NaO₄ 357.16; 379.14; 713.31; 735.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 357.18; 379.15; 713.32; 735.31.

Example 04-03 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(pyridin-4-yl)benzamide(04-03)

The title compound was prepared from Example 01-03 and 4-aminopyridineaccording to the procedure of Example 04-01; 1.1 mmol scale yielded 60mg after recrystallization from MeOH (18% yield). ¹H NMR (D6-DMSO) δ1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.73 (m, 2H), 7.49-7.54 (m, 2H),7.72 (d, J=7.1 Hz, 1H), 7.80 (s, 3H), 8.49 (d, J=4.7 Hz, 2H), 9.17 (s,1H), 10.62 (s, 1H). LCMS t=3.0 min, m/z Calcd for C₁₈H₁₈N₃O₂;C₁₈H₁₇N₃NaO₂; C₃₆H₃₄N₆NaO₄ 308.14; 330.12; 637.25 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 308.17; 330.14; 637.24.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 04N-(4-Methoxyphenyl)-3-((2-methyl-3- H H OCH₃oxocyclopent-1-en-1-yl)amino)benzamide 053-((2-Methyl-3-oxocyclopent-1-en-1- CH₃ H Hyl)amino)-N-(o-tolyl)benzamide 06 3-((2-Methyl-3-oxocyclopent-1-en-1- HCH₃ H yl)amino)-N-(m-tolyl)benzamide 073-((2-Methyl-3-oxocyclopent-1-en-1- H H CH₃yl)amino)-N-(p-tolyl)benzamide 08 N-(2-Fluorophenyl)-3-((2-methyl-3- F HH oxocyclopent-1-en-1-yl)amino)benzamide 09N-(3-Bromophenyl)-3-((2-methyl-3-oxocyclopent- H Br H1-en-1-yl)amino)benzamide 10N-(4-Bromophenyl)-3-((2-methyl-3-oxocyclopent- H H Br1-en-1-yl)amino)benzamide 113-((2-Methyl-3-oxocyclopent-1-en-1-yl)amino)-N- H CF₃ H(3-(trifluoromethyl)phenyl)benzamide 123-((2-Methyl-3-oxocyclopent-1-en-1-yl)amino)-N- H H CF₃(4-(trifluoromethyl)phenyl)benzamide

Example 04-04 Preparation ofN-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-04)

Method B; IBCF (0.98 eq) was added to Example 01-03 (250 mg, 1.1 mmol,1.0 eq) stirring in CH₂Cl₂ (3.0 mL), in a screw-capped vial. NMM (0.95eq) was added at 0° C. After stirring for 1 h, 4-aminoanisole (163 mg,1.0 eq) was added, sealed, and stirred for 18 h at rt. Crude materialswere added directly to KP-Sil™ columns (10 g) with products separatingfrom impurities using stepwise gradients on the Biotage®-Isolera Fourinstrument, monitoring UV Trace at 254/365 nm. The stepwise gradientutilized two, or three, solvents (acetone, hexanes, EtOAc, or MeOH)running from non-polar to polar steps. Typical increments used werehexanes:EtOAc (H:E) steps 1:1-1:3-1:19-100% EtOAc, then when necessary2-5% increments of MeOH were applied. Eluting Solvent System (ESS) isthe solvent step which eluted the product and is indicated below in thefollowing format ESS=H:E (X:X), or the percentage of MeOH (%) in EtOAc.Subsequent triturations or recrystallizations were performed fromsuitable solvents. The reaction on a 1.1 mmol scale yielded 30 mg of thetitle compound after chromatography (ESS=EtOAc:acetone (1:3)) andrecrystallization from EtOAc (8% yield). ¹H NMR (D6-DMSO) δ 1.59 (s,3H), 2.23-2.25 (m, 2H), 2.70-2.72 (m, 2H), 3.75 (s, 3H), 6.93 (d, J=8.7Hz, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.67 (d, J=8.7Hz, 2H), 7.70 (d, J=7.5 Hz, 1H), 7.78 (s, 1H), 9.14 (s, 1H), 10.14 (s,1H). LCMS t=5.6 min, m/z Calcd for C₂₀H₂₁N₂O₃; C₂₀H₂₀N₂NaO₃; C₄₀H₄₁N₄O₆;C₄₀H₄₀N₄NaO₆ 337.16; 359.14; 673.30; 695.28 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 337.19; 359.17; 673.33; 695.32.

Example 04-05 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-05)

The title compound was prepared from Example 01-03 and o-toluidineaccording to the procedure of Example 04-04; 1.1 mmol scale yielded 10mg after chromatography (ESS=H:E (1:1)) and recrystallization from MeOH(3% yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.23-2.25 (m, 5H),2.71-2.73 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H), 7.28(d, J=7.2 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.50(t, J=7.7 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.81 (s, 1H), 9.13 (s, 1H),9.90 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂;C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16; 343.14; 641.31; 663.29 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 321.19; 343.16; 641.31; 663.32.

Example 04-06 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide(04-06)

The title compound was prepared from Example 01-03 and m-toluidineaccording to the procedure of Example 04-04; 1.1 mmol scale yielded 30mg after chromatography (ESS=EtOAc) and recrystallization from MeOH (9%yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.22-2.25 (m, 2H), 2.31 (s,3H), 2.70-2.72 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H),7.46 (d, J=8.2 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H),7.62 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 9.15 (s, 1H), 10.18(s, 1H). LCMS t=5.8 min, m/z Calcd for C₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂;C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16; 343.14; 641.31; 663.29 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 321.19; 343.16; 641.31; 663.29.

Example 04-07 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide(04-07)

The title compound was prepared from Example 01-03 and p-toluidineaccording to the procedure of Example 04-04; 1.1 mmol scale yielded 10mg after chromatography (ESS=EtOAc) and recrystallization from CHCl₃ (3%yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.22-2.25 (m, 2H), 2.28 (s,3H), 2.70-2.72 (m, 2H), 7.16 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H),7.50 (t, J=7.8 Hz, 1H), 7.65 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.6 Hz, 1H),7.79 (s, 1H), 9.14 (s, 1H), 10.18 (s, 1H). LCMS t=5.8 min, m/z Calcd forC₂₀H₂₁N₂O₂; C₂₀H₂₀N₂NaO₂; C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16; 343.14;641.31; 663.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 321.19; 343.16;641.31; 663.30.

Example 04-08 Preparation ofN-(2-fluorophenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-08)

The title compound was prepared from Example 01-03 and 2-fluoroanilineaccording to the procedure of Example 04-04; 1.1 mmol scale yielded 40mg after chromatography (ESS=EtOAc) and recrystallization from MeOH (11%yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.22-2.25 (m, 2H), 2.70-2.72(m, 2H), 7.21-7.25 (m, 1H), 7.29-7.33 (m, 2H), 7.48-7.52 (m, 2H), 7.59(t, J=7.2 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 9.15 (s, 1H),10.14 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₁₉H₁₈FN₂O₂; C₁₉H₁₇FN₂NaO₂;C₃₈H₃₅F₂N₄O₄; C₃₈H₃₄F₂N₄NaO₄ 325.14; 347.12; 649.26; 671.24 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 325.16; 347.14; 649.26; 671.26.

Example 04-09 Preparation ofN-(3-bromophenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-09)

The title compound was prepared from Example 01-03 and 3-bromoanilineaccording to the procedure of Example 04-04; 1.1 mmol scale yielded 40mg after chromatography (ESS=EtOAc) and recrystallization from MeOH (9%yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.73(m, 2H), 7.31-7.34 (m, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.52 (t, J=7.8 Hz,1H), 7.71 (d, J=7.5 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.79 (s, 1H), 8.11(s, 1H), 9.16 (s, 1H), 10.40 (s, 1H). LCMS t=5.9 min, m/z Calcd forC₁₉H₁₈BrN₂O₂; C₁₉H₁₇BrN₂NaO₂; C₃₈H₃₅BrN₄O₄; C₃₈H₃₄BrN₄NaO₆ 385.06,387.05; 407.04, 409.04; 771.10; 793.08 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 385.06, 387.06; 407.04, 409.04; 771.12; 793.11.

Example 04-10 Preparation ofN-(4-bromophenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-10)

The title compound was prepared from Example 01-03 and 4-bromoanilineaccording to the procedure of Example 04-04; 1.1 mmol scale yielded 10mg after chromatography (ESS=EtOAc) and recrystallization from CHCl₃ (2%yield). ¹H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.26 (m, 2H), 2.71-2.73(m, 2H), 7.47-7.48 (m, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.55 (d, J=8.8 Hz,2H), 7.70 (d, J=7.7 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.79 (s, 1H), 9.14(s, 1H), 10.38 (s, 1H). LCMS t=5.9 min, m/z Calcd for C₁₉H₁₈BrN₂O₂;C₁₉H₁₇BrN₂NaO₂; C₃₈H₃₅BrN₄O₄; C₃₈H₃₄BrN₄NaO₆ 385.06, 387.05; 407.04,409.04; 771.10; 793.08 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 385.06,387.06; 407.04, 409.03; 771.12; 793.11.

Example 04-11 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(3-(trifluoromethyl)phenyl)-benzamide(04-11)

The title compound was prepared from Example 01-03 and3-(trifluoromethyl)aniline according to the procedure of Example 04-04;1.1 mmol scale yielded 30 mg after chromatography (ESS=EtOAc) andrecrystallization from CHCl₃ (7% yield). ¹H NMR (D6-DMSO) δ 1.60 (s,3H), 2.23-2.25 (m, 2H), 2.71-2.73 (m, 2H), 7.46-7.50 (m, 2H), 7.53 (t,J=7.8 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.82 (s,1H), 8.06 (d, J=8.2 Hz, 1H), 8.25 (s, 1H), 9.16 (s, 1H), 10.56 (s, 1H).LCMS t=6.1 min, m/z Calcd for C₂₀H₁₈F₃N₂O₂; C₂₀H₁₇F₃N₂NaO₂;C₄₀H₃₅F₆N₄O₄; C₄₀H₃₄F₆N₄NaO₆ 375.13; 397.11; 749.26; 771.24 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 375.14; 397.12; 749.27; 771.26.

Example 04-12 Preparation of3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(4-(trifluoromethyl)phenyl)-benzamide(04-12)

The title compound was prepared from Example 01-03 and3-(trifluoromethyl)aniline according to the procedure of Example 04-04;1.1 mmol scale yielded 10 mg after chromatography (ESS=EtOAc) andrecrystallization from CHCl₃ (2% yield). ¹H NMR (D6-DMSO) δ 1.60 (s,3H), 2.23-2.25 (m, 2H), 2.71-2.73 (m, 2H), 7.49-7.50 (m, 1H), 7.53 (t,J=7.7 Hz, 1H), 7.72-7.75 (m, 3H), 7.81 (s, 1H), 8.01 (d, J=8.5 Hz, 2H),9.16 (s, 1H), 10.59 (s, 1H). LCMS t=6.1 min, m/z Calcd for C₂₀H₁₈F₃N₂O₂;C₂₀H₁₇F₃N₂NaO₂; C₄₀H₃₄F₆N₄NaO₆ 375.13; 397.11; 771.24 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 375.16; 397.12; 771.26.

Example 04-13 Preparation of3-chloro-N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-13)

Method C; NMM (1.2 eq) and IBCF (1.2 eq) were added to Example 02-02(100 mg, 0.38 mmol, 1.0 eq), stirring in CH₂Cl₂ (10 mL), in ascrew-capped vial. After stirring for 30 min amine, methylamine (2M, 225mL, 0.45 mmol, 1.2 eq), and a second aliquot of NMM (1.2 eq) were added,sealed, and stirred at rt for 48 h. Crude materials were added directlyto KP-Sil™ columns (10 g) with products separating from impurities usingstepwise gradients (see Example 04-04 Method B) on the Biotage®-IsoleraFour instrument, monitoring UV Trace at 254/365 nm. Some reactionsperformed at higher concentrations allowed the crude solid product toprecipitate. In these cases the purification was filtration with CH₂Cl₂,H2O, and diethyl ether rinsing. The reaction on a 0.38 mmol scaleyielded 35 mg of the title compound after chromatography (ESS=MeOH (6%))and EtOAc trituration (33% yield). ¹H NMR (D6-DMSO) δ 1.45 (s, 3H),2.21-2.23 (m, 2H), 2.47-2.49 (m, 2H), 2.78 (s, 3H), 7.44 (d, J=8.3 Hz,1H), 7.80 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 8.56-8.58 (m, 1H), 8.93 (s,1H). LCMS t=5.1 min, m/z Calcd for C₁₄H₁₆ClN₂O₂; C₁₄H₁₅ClN₂NaO₂;C₂₈H₃₁Cl₂N₄O₄; C₂₈H₃₀Cl₂N₄NaO₄ 279.09; 301.07; 557.17; 579.15 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 279.14; 301.11; 557.16; 579.15.

Example 04-14 Preparation of3-chloro-N-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-14)

The title compound was prepared from Example 02-02 and cyclohexylamineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 56mg after chromatography (ESS=EtOAc) and EtOAc trituration (43% yield).¹H NMR (D6-DMSO) δ 1.10-1.18 (m, 1H), 1.23-1.34 (m, 4H), 1.45 (s, 3H),1.61 (d, J=12.1 Hz, 1H), 1.73 (s, 2H), 1.81 (s, 2H), 2.20-2.23 (m, 2H),2.46-2.48 (m, 2H), 3.75 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.2Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 8.34 (d, J=7.8 Hz, 1H), 8.95 (s, 1H).LCMS t=6.0 min, m/z Calcd for C₁₉H₂₄ClN₂O₂; C₁₉H₂₃ClN₂NaO₂;C₃₆H₄₇Cl₂N₄O₄; C₃₆H₄₇Cl₂N₄NaO₄ 347.15; 369.13; 693.30; 715.28 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 347.17; 369.15; 693.32; 715.30.

Example 04-15 Preparation of3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)-benzamide(04-15)

The title compound was prepared from Example 02-02 and1-aminonaphthalene according to the procedure of Example 04-13; 0.38mmol scale yielded 25 mg after chromatography (ESS=H:E (1:19)) and EtOActrituration (17% yield). ¹H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.24-2.26 (m,2H), 2.54-2.56 (m, 2H), 7.52-7.61 (m, 4H), 7.89 (d, J=8.0 Hz, 1H),7.98-8.01 (m, 3H), 8.06 (d, J=7.7 Hz, 1H), 8.27 (s, 1H), 9.03 (s, 1H),10.55 (s, 1H). LCMS t=5.9 min, m/z Calcd for C₂₃H₂₀ClN₂O₂;C₂₃H₁₉ClN₂NaO₂; C₄₆H₃₉Cl₂N₄O₄; C₄₆H₃₈Cl₂N₄NaO₄ 391.12; 413.10; 781.23;803.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 391.22; 413.11; 781.26;803.25.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 163-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- H H Hyl)amino)-N-phenylbenzamide 173-Chloro-N-(2-methoxyphenyl)-4-((2-methyl-3- OCH₃ H Hoxocyclopent-1-en-1-yl)amino)benzamide 183-Chloro-N-(3-methoxyphenyl)-4-((2-methyl-3- H OCH₃ Hoxocyclopent-1-en-1-yl)amino)benzamide 193-Chloro-N-(4-methoxyphenyl)-4-((2-methyl-3- H H OCH₃oxocyclopent-1-en-1-yl)amino)benzamide 203-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- CH₃ H Hyl)amino)-N-(o-tolyl)benzamide 213-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- H CH₃ Hyl)amino)-N-(m-tolyl)benzamide 223-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- H H CH₃yl)amino)-N-(p-tolyl)benzamide

Example 04-16 Preparation of3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide(04-16)

The title compound was prepared from Example 02-02 and aniline accordingto the procedure of Example 04-13; 0.38 mmol scale yielded 20 mg afterchromatography (ESS=H:E (1:19)) and EtOAc trituration (16% yield). ¹HNMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.25 (m, 2H), 2.50-2.51 (m, 2H), 7.12(t, J=7.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 2H), 7.50 (d, J=8.3 Hz, 1H), 7.77(d, J=7.9 Hz, 2H), 7.94 (dd, J=8.2, 1.4 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H),9.00 (s, 1H), 10.34 (s, 1H). LCMS t=5.8 min, m/z Calcd for C₁₉H₁₈ClN₂O₂;C₁₉H₁₇ClN₂NaO₂; C₃₈H₃₄Cl₂N₄NaO₄ 341.11; 363.09; 703.19 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 341.13; 363.10; 703.20.

Example 04-17 Preparation of3-chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-17)

The title compound was prepared from Example 02-02 and o-anisidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 55mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (39%yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.22-2.25 (m, 2H), 2.50-2.52(m, 2H), 3.83 (s, 3H), 6.97 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H),7.21 (t, J=7.6 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H),7.94 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 9.00 (s, 1H), 9.67 (s, 1H). LCMSt=5.9 min, m/z Calcd for C₂₀H₂₀ClN₂O₃; C₂₀H₁₉ClN₂NaO₃; C₄₀H₃₉Cl₂N₄O₆;C₄₀H₃₈Cl₂N₄NaO₆ 371.11; 393.10; 741.22; 763.21 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 371.13; 393.11; 741.26; 763.24.

Example 04-18 Preparation of3-chloro-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-18)

The title compound was prepared from Example 02-02 and m-anisidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 3mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (2%yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.25 (m, 2H), 2.50-2.52(m, 2H), 3.76 (s, 3H), 6.70 (d, J=8.3 Hz, 1H), 7.26 (t, J=8.3 Hz, 1H),7.37 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.93 (dd,J=8.3, 1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 9.00 (s, 1H), 10.30 (s, 1H).LCMS t=5.8 min, m/z Calcd for C₂₀H₂₀ClN₂O₃; C₂₀H₁₉ClN₂NaO₃;C₄₀H₃₉Cl₂N₄O₆; C₄₀H₃₈Cl₂N₄NaO₆ 371.11; 393.10; 741.22; 763.21 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 371.13; 393.11; 741.26; 763.23.

Example 04-19 Preparation of3-chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-19)

The title compound was prepared from Example 02-02 and 4-aminoanisoleaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 5mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (4%yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.22-2.25 (m, 2H), 2.50-2.51(m, 2H), 3.75 (s, 3H), 6.94 (d, J=8.9 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H),7.66 (d, J=8.9 Hz, 2H), 7.93 (dd, J=8.3, 1.2 Hz, 1H), 8.12 (s, 1H), 8.98(s, 1H), 10.22 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₂₀H₂₀ClN₂O₃;C₂₀H₁₉ClN₂NaO₃; C₄₀H₃₉Cl₂N₄O₆; C₄₀H₃₈Cl₂N₄NaO₆ 371.11; 393.10; 741.22;763.21 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 371.13; 393.10; 741.24;763.23.

Example 04-20 Preparation of3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-20)

The title compound was prepared from Example 02-02 and o-toluidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 45mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (32%yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.25 (m, 5H), 2.50-2.51(m, 2H), 7.18-7.23 (m, 2H), 7.28 (d, J=7.3 Hz, 1H), 7.32 (d, J=7.5 Hz,1H), 7.50 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 8.14 (s, 1H), 8.99(s, 1H), 10.02 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₂₀H₂₀ClN₂O₂;C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄ 355.12; 377.10; 709.23;731.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.14; 377.12; 709.25;731.24.

Example 04-21 Preparation of3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide(04-21)

The title compound was prepared from Example 02-02 and m-toluidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 42mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (30%yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.22-2.25 (m, 2H), 2.31 (s,3H), 2.50-2.51 (m, 2H), 6.94 (d, J=7.4 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H),7.49 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.93 (d,J=8.3 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.98 (s, 1H), 10.26 (s, 1H). LCMSt=5.9 min, m/z Calcd for C₂₀H₂₀ClN₂O₂; C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄;C₄₀H₃₈Cl₂N₄NaO₄ 355.12; 377.10; 709.23; 731.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 355.14; 377.12; 709.25; 731.24.

Example 04-22 Preparation of3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide(04-22)

The title compound was prepared from Example 02-02 and p-toluidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 25mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (18%yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.24 (m, 2H), 2.29 (s,3H), 2.50-2.51 (m, 2H), 7.17 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H),7.64 (d, J=8.1 Hz, 2H), 7.93 (d, J=8.2 Hz, 1H), 8.13 (s, 1H), 8.96 (s,1H), 10.25 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.7, 20.5, 25.7, 32.7, 110.8,120.5, 127.2, 128.8, 128.9, 129.0, 132.9, 136.4, 139.4, 163.3, 168.7,202.7. LCMS t=5.9 min, m/z Calcd for C₂₀H₂₀ClN₂O₂; C₂₀H₁₉ClN₂NaO₂;C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄ 355.12; 377.10; 709.23; 731.22 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.12; 377.10; 709.21; 731.20.

Example 04-23 Preparation of(1R,4R)—N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide(04-23)

The title compound was prepared from Example 01-33 and methylamineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 40mg after chromatography (ESS=MeOH (15%)) and EtOAc trituration (38%yield). ¹H NMR (D6-DMSO) δ 1.33-1.50 (m, 9H), 1.73 (d, J=12.0 Hz, 2H),1.84 (d, J=10.6 Hz, 2H), 2.04-2.09 (m, 1H), 2.09-2.11 (2H), 2.54 (d,J=4.5 Hz, 2H), 3.25-3.30 (m, 1H), 6.84-6.87 (m, 1H), 7.70 (d, J=4.3 Hz,1H). LCMS t=1.2 min, m/z Calcd for C₁₄H₂₃N₂O₂; C₁₄H₂₂N₂NaO₂; C₂₈H₄₅N₄O₄;C₂₈H₄₄N₄NaO₄ 251.18; 273.16; 501.34; 523.33 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 251.28; 273.25; 501.41; 523.40.

Example 04-24 Preparation of(1R,4R)—N-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide(04-24)

The title compound was prepared from Example 01-33 and cyclohexylamineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 75mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (56%yield). ¹H NMR (D6-DMSO) δ 1.10-1.18 (m, 4H), 1.20-1.28 (m, 2H),1.30-1.40 (m, 2H), 1.40-1.50 (5H), 1.54 (d, J=10.8 Hz, 1H), 1.62-1.75(m, 7H), 1.83 (d, J=10.4 Hz, 1H), 2.00-2.08 (m, 1H), 2.10-2.13 (m, 2H),3.46-3.53 (m, 1H), 6.85-6.67 (m, 1H), 7.57 (d, J=7.4 Hz, 1H). LCMS t=5.4min, m/z Calcd for C₁₉H₃₁N₂O₂; C₁₉H₃₀N₂NaO₂; C₃₈H₆₁N₄NaO₄; C₃₈H₆₀N₄NaO₄319.24; 341.22; 637.47; 659.45 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found319.32; 341.29; 637.57; 659.60.

Example 04-25 Preparation of(1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)cyclohexanecarboxamide(04-25)

The title compound was prepared from Example 01-33 and1-aminonaphthalene according to the procedure of Example 04-13; 0.42mmol scale yielded 23 mg after chromatography (ESS=MeOH (8%)) and EtOActrituration (15% yield). ¹H NMR (D6-DMSO) δ 1.45-1.55 (m, 5H), 1.62 (q,J=12.1 Hz, 2H), 1.94 (d, J=10.8 Hz, 2H), 2.01 (d, J=12.7 Hz, 2H),2.11-2.13 (m, 2H), 2.51-2.55 (m, 3H), 3.35-3.45 (m, 1H), 6.92 (d, J=7.7Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.65 (d, J=7.3 Hz,1H), 7.76 (d, J=8.1 Hz, 1H), 7.94 (d, J=7.1 Hz, 1H), 8.04 (d, J=7.7 Hz,1H), 9.85 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₂₃H₂₇N₂O₂;C₂₃H₂₆N₂NaO₂; C₄₆H₅₃N₄O₄; C₄₆H₅₂N₄NaO₄ 363.21; 385.18; 725.41; 747.39[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 363.34; 385.25; 725.53;747.52.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 26(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1- H H Hyl)amino)-N-phenylcyclohexanecarboxamide 27(1R,4R)-N-(2-Methoxyphenyl)-4-((2-methyl-3- OCH₃ H Hoxocyclopent-1-en-1- yl)amino)cyclohexanecarboxamide 28(1R,4R)-N-(3-Methoxyphenyl)-4-((2-methyl-3- H OCH₃ Hoxocyclopent-1-en-1- yl)amino)cyclohexanecarboxamide 29(1R,4R)-N-(4-Methoxyphenyl)-4-((2-methyl-3- H H OCH₃oxocyclopent-1-en-1- yl)amino)cyclohexanecarboxamide 30(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1- CH₃ H Hyl)amino)-N-(o-tolyl)cyclohexanecarboxamide 31(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1- H CH₃ Hyl)amino)-N-(m-tolyl)cyclohexanecarboxamide 32(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1- H H CH₃yl)amino)-N-(p-tolyl)cyclohexanecarboxamide 33(1R,4R)-N-(3-Fluorophenyl)-4-((2-methyl-3- H F H oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide 34(1R,4R)-N-(4-Chlorophenyl)-4-((2-methyl-3- H H Cl oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide

Example 04-26 Preparation of(1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylcyclohexane-carboxamide(04-26)

The title compound was prepared from Example 01-33 and aniline accordingto the procedure of Example 04-13; 0.42 mmol scale yielded 65 mg afterchromatography (ESS=MeOH (10%)) and EtOAc trituration (50% yield). ¹HNMR (D6-DMSO) δ 1.38-1.60 (m, 8H), 1.83-1.98 (m, 5H), 2.08-2.18 (m, 2H),2.28-2.39 (m, 1H), 3.28-3.30 (m, 1H), 6.89 (s, 1H), 7.01 (s, 1H), 7.28(s, 2H), 7.60 (s, 2H), 9.85 (s, 1H). LCMS t=5.4 min, m/z Calcd forC₁₉H₂₅N₂O₂; C₁₉H₂₄N₂NaO₂; C₃₈H₄₉N₄O₄; C₃₈H₄₈N₄NaO₄ 313.19; 335.17;625.37; 647.36 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 313.27; 335.25;625.47; 647.46.

Example 04-27 Preparation of(1R,4R)—N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide(04-27)

The title compound was prepared from Example 01-33 and o-anisidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 75mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (52%yield). ¹H NMR (D6-DMSO) δ 1.40-1.56 (m, 8H) 1.84-1.89 (m, 5H),2.10-2.12 (m, 2H), 2.47-2.52 (m, 2H), 3.83 (s, 3H), 6.86-6.91 (m, 2H),7.01-7.07 (m, 2H), 7.94 (d, J=7.8 Hz, 1H), 9.02 (s, 1H). LCMS t=5.5 min,m/z Calcd for C₂₀H₂₇N₂O₃; C₂₀H₂₆N₂NaO₃; C₄₀H₅₃N₄O₆; C₄₀H₅₂N₄NaO₆ 343.20;365.18; 685.40; 707.38 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 343.30;365.25; 685.51; 707.57.

Example 04-28 Preparation of(1R,4R)—N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide(04-28)

The title compound was prepared from Example 01-33 and m-anisidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 70mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (49%yield). ¹H NMR (D6-DMSO) δ 1.40-1.57 (m, 7H), 1.85-1.91 (m, 5H),2.11-2.13 (m, 2H), 2.28 (t, J=11.6 Hz, 1H), 2.52-2.54 (m, 2H), 3.71 (s,3H), 6.60 (d, J=7.6 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 7.13 (d, J=7.8 Hz,1H), 7.18 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 9.84 (s, 1H). LCMS t=5.4 min,m/z Calcd for C₂₀H₂₇N₂O₃; C₂₀H₂₆N₂NaO₃; C₄₀H₅₃N₄O₆; C₄₀H₅₂N₄NaO₆ 343.20;365.18; 685.40; 707.38 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 343.27;365.25; 685.51; 707.50.

Example 04-29 Preparation of(1R,4R)—N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide(04-29)

The title compound was prepared from Example 01-33 and p-anisidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 35mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (24%yield). ¹H NMR (D6-DMSO) δ 1.38-1.58 (m, 7H), 1.84-1.90 (m, 5H),2.10-2.12 (m, 2H), 2.25 (t, J=11.7 Hz, 1H), 2.51-2.54 (m, 2H), 3.71 (s,3H), 6.84-6.89 (m, 3H), 7.50 (d, J=8.7 Hz, 2H), 9.71 (s, 1H). LCMS t=5.3min, m/z Calcd for C₂₀H₂₇N₂O₃; C₂₀H₂₆N₂NaO₃; C₄₀H₅₃N₄O₆; C₄₀H₅₂N₄NaO₆343.20; 365.18; 685.40; 707.38 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found343.27; 365.25; 685.50; 707.49.

Example 04-30 Preparation of(1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)cyclohexanecarboxamide(04-30)

The title compound was prepared from Example 01-33 and o-toluidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 22mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (16%yield). ¹H NMR (D6-DMSO) δ 1.41-1.59 (m, 7H), 1.89-1.92 (m, 4H),2.11-2.13 (m, 2H), 2.18 (s, 3H), 2.37 (t, J=10.9 Hz, 1H), 2.51-2.53 (m,2H), 6.88-6.93 (m, 1H), 7.07 (t, J=6.9 Hz, 1H), 7.14 (t, J=7.1 Hz, 1H),7.19 (d, J=7.1 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 9.22 (s, 1H). LCMS t=5.3min, m/z Calcd for C₂₀H₂₇N₂O₂; C₂₀H₂₆N₂NaO₂; C₄₀H₅₃N₄O₄; C₄₀H₅₂N₄NaO₄327.21; 349.19; 653.41; 675.39 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found327.28; 349.26; 653.50; 675.49.

Example 04-31 Preparation of(1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)cyclohexanecarboxamide(04-31)

The title compound was prepared from Example 01-33 and m-toluidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 70mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (51%yield). ¹H NMR (D6-DMSO) δ 1.38-1.58 (m, 7H), 1.84-1.91 (m, 4H),2.10-2.12 (m, 2H), 2.26-2.31 (m, 4H), 2.51-2.53 (m, 2H), 3.33-3.35 (m,1H), 6.83 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 7.5 (d, J=7.8 Hz,1H), 7.36 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 9.77 (s, 1H). LCMS t=5.5 min,m/z Calcd for C₂₀H₂₇N₂O₂; C₂₀H₂₆N₂NaO₂; C₄₀H₅₃N₄O₄; C₄₀H₅₂N₄NaO₄ 327.21;349.19; 653.41; 675.39 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 327.28;349.26; 653.50; 675.49.

Example 04-32 Preparation of(1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)-cyclohexanecarboxamide(04-32)

The title compound was prepared from Example 01-33 and p-toluidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 60mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (44%yield). ¹H NMR (D6-DMSO) δ 1.28-1.58 (m, 7H), 1.84-1.90 (m, 4H),2.10-2.12 (m, 2H), 2.23-2.30 (m, 4H), 2.51-2.53 (m, 2H), 3.30-3.35 (m,1H), 6.89 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.2 Hz,2H), 9.76 (s, 1H). ¹³C NMR (D6-DMSO) δ 6.8, 20.4, 23.8, 28.1, 32.5,32.7, 43.8, 51.6, 105.0, 119.0, 129.0, 131.8, 136.9, 172.1, 173.6,200.0. LCMS t=5.6 min, m/z Calcd for C₂₀H₂₇N₂O₂; C₂₀H₂₆N₂NaO₂;C₄₀H₅₃N₄O₄; C₄₀H₅₂N₄NaO₄ 327.21; 349.19; 653.41; 675.39 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 327.28; 349.26; 653.50; 675.49.

Example 04-33 Preparation of(1R,4R)—N-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide(04-33)

The title compound was prepared from Example 01-33 and m-fluoroanilineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 72mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (52%yield). ¹H NMR (D6-DMSO) δ 1.38-1.57 (m, 7H), 1.86-1.91 (m, 4H),2.10-2.12 (m, 2H), 2.29 (t, J=11.9 Hz, 1H), 2.51-2.53 (m, 2H), 3.33-2.35(m, 1H), 6.83-6.90 (m, 2H), 7.29-7.33 (m, 2H), 7.61 (d, J=11.9 Hz, 1H),10.08 (s, 1H). LCMS t=5.5 min, m/z Calcd for C₁₉H₂₄FN₂O₂; C₁₉H₂₃FN₂NaO₂;C₃₈H₄₇F₂N₄O₄; C₃₈H₄₆F₂N₄NaO₄ 331.18; 353.16; 661.36; 683.34 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 331.27; 353.23; 661.45; 683.44.

Example 04-34 Preparation of(1R,4R)—N-(4-chlorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide(04-34)

The title compound was prepared from Example 01-33 and p-chloroanilineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 30mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (21%yield). ¹H NMR (D6-DMSO) δ 1.38-1.58 (m, 7H), 1.86-1.91 (m, 4H),2.10-2.12 (m, 2H), 2.28 (t, J=11.9 Hz, 1H), 2.51-2.53 (m, 2H), 3.33-3.35(m, 1H), 6.88 (d, J=8.3 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.7Hz, 2H), 10.01 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₁₉H₂₄ClN₂O₂;C₁₉H₂₃ClN₂NaO₂; C₃₈H₄₇Cl₂N₄O₄; C₃₈H₄₆Cl₂N₄NaO₄ 347.15; 369.13; 693.30;715.28 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 347.22; 369.20; 693.40;715.39.

Example 04-35 Preparation of(1S,4S)—N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide(04-35)

The title compound was prepared from Example 01-34 and methylamineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 11mg after chromatography (ESS=MeOH (12%)) and EtOAc trituration (10%yield). ¹H NMR (D6-DMSO) δ 1.45-1.52 (m, 5H), 1.58-1.65 (m, 4H),1.93-2.00 (m, 2H), 2.09-2.13 (m, 2H), 2.26-2.30 (m, 1H), 2.49-2.51 (m,2H), 2.58 (d, J=3.9 Hz, 3H), 3.33-3.35 (m, 1H), 6.80-6.86 (m, 1H),7.60-7.66 (m, 1H). LCMS t=1.4 min, m/z Calcd for C₁₄H₂₃N₂O₂;C₁₄H₂₂N₂NaO₂; C₂₈H₄₄N₄NaO₄ 251.18; 273.16; 523.33 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 251.28; 273.25; 523.40.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 36(1S,4S)-4-((2-Methyl-3-oxocyclopent-1-en-1- H H Hyl)amino)-N-phenylcyclohexanecarboxamide 37(1S,4S)-N-(2-Methoxyphenyl)-4-((2-methyl-3- OCH₃ H Hoxocyclopent-1-en-1- yl)amino)cyclohexanecarboxamide 38(1S,4S)-N-(3-Methoxyphenyl)-4-((2-methyl-3- H OCH₃ Hoxocyclopent-1-en-1- yl)amino)cyclohexanecarboxamide 39(1S,4S)-4-((2-Methyl-3-oxocyclopent-1-en-1- H CH₃ Hyl)amino)-N-(m-tolyl)cyclohexanecarboxamide 40(1S,4S)-4-((2-Methyl-3-oxocyclopent-1-en-1- H H CH₃yl)amino)-N-(p-tolyl)cyclohexanecarboxamide 41(1S,4S)-N-(3-Fluorophenyl)-4-((2-methyl-3- H F H oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide 42(1S,4S)-N-(4-Chlorophenyl)-4-((2-methyl-3- H H Cl oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide

Example 04-36 Preparation of(1S,4S)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylcyclohexane-carboxamide(04-36)

The title compound was prepared from Example 01-34 and aniline accordingto the procedure of Example 04-13; 0.42 mmol scale yielded 16 mg afterchromatography (ESS=MeOH (7%)) and EtOAc trituration (12% yield). ¹H NMR(D6-DMSO) δ 1.45-1.55 (m, 3H), 1.61-1.68 (m, 5H), 1.74-1.81 (m, 2H),2.00-2.18 (m, 2H), 2.09-2.12 (m, 2H), 2.53-2.55 (m, 2H), 3.40-3.60 (m,1H), 6.88 (s, 1H), 7.02 (t, J=7.4 Hz, 1H), 7.28 (t, J=7.9 Hz, 2H), 7.62(d, J=7.9 Hz, 2H), 9.74 (s, 1H). LCMS t=5.5 min, m/z Calcd forC₁₉H₂₅N₂O₂; C₁₉H₂₄N₂NaO₂; C₃₈H₄₈N₄NaO₄ 313.19; 335.17; 647.36 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 313.28; 335.25; 647.46.

Example 04-37 Preparation of(1S,4S)—N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide(04-37)

The title compound was prepared from Example 01-34 and o-anisidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 60mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (42%yield). ¹H NMR (D6-DMSO) δ 1.45-1.54 (m, 3H), 1.60-1.69 (m, 5H),1.71-1.77 (m, 2H), 1.98-2.05 (m, 2H), 2.08-2.12 (m, 2H), 2.51-2.53 (m,1H), 2.68-2.72 (m, 1H), 3.42-3.58 (m, 1H), 3.83 (s, 3H), 6.85-6.92 (m,2H), 7.02-7.08 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.87 (s, 1H). LCMS t=5.6min, m/z Calcd for C₂₀H₂₇N₂O₃; C₂₀H₂₆N₂NaO₃; C₄₀H₅₂N₄NaO₆ 343.20;365.18; 707.38 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 343.28; 365.26; 707.52.

Example 04-38 Preparation of(1S,4S)—N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide(04-38)

The title compound was prepared from Example 01-34 and m-anisidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 3mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (2%yield). ¹H NMR (D6-DMSO) δ 1.45-1.53 (m, 3H), 1.59-1.69 (m, 5H),1.73-1.78 (m, 2H), 1.99-2.08 (m, 2H), 2.09-2.12 (m, 2H), 2.49-2.51 (m,2H), 3.45-3.55 (m, 1H), 3.72 (s, 3H), 6.60 (d, J=6.8 Hz, 1H), 6.88-6.92(m, 1H), 7.14-7.20 (m, 2H), 7.37 (s, 1H), 9.74 (s, 1H). LCMS t=5.6 min,m/z Calcd for C₂₀H₂₇N₂O₃; C₂₀H₂₆N₂NaO₃; C₄₀H₅₂N₄NaO₆ 343.20; 365.18;707.38 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 343.20; 365.18; 707.35.

Example 04-39 Preparation of(1S,4S)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)-cyclohexanecarboxamide(04-39)

The title compound was prepared from Example 01-34 and m-toluidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 1mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (1%yield). ¹H NMR (D6-DMSO) δ 1.46-1.53 (m, 3H), 1.59-1.69 (m, 5H),1.73-1.81 (m, 2H), 2.00-2.07 (m, 2H), 2.09-2.14 (m, 2H), 2.26 (s, 3H),2.50-2.53 (m, 2H), 3.40-3.53 (m, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.85-6.90(m, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.48 (s, 1H),9.66 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₂₀H₂₇N₂O₂; C₂₀H₂₆N₂NaO₂;C₄₀H₅₂N₄NaO₄ 327.21; 349.19; 675.39 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found327.29; 349.25; 675.52.

Example 04-40 Preparation of(1S,4S)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)-cyclohexanecarboxamide(04-40)

The title compound was prepared from Example 01-34 and p-toluidineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 1mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (1%yield). ¹H NMR (D6-DMSO) δ 1.46-1.53 (m, 3H), 1.58-1.68 (m, 5H),1.73-1.80 (m, 2H), 2.00-2.07 (m, 2H), 2.09-2.13 (m, 2H), 2.24 (s, 3H),2.50-2.53 (m, 2H), 3.40-3.53 (m, 1H), 6.87-6.92 (m, 1H), 7.08 (d, J=7.9Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 9.65 (s, 1H). LCMS t=5.7 min, m/z Calcdfor C₂₀H₂₇N₂O₂; C₂₀H₂₆N₂NaO₂; C₄₀H₅₃N₄O₄; C₄₀H₅₂N₄NaO₄ 327.21; 349.19;653.41; 675.39 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 327.29; 349.26;653.50; 675.49.

Example 04-41 Preparation of(1S,4S)—N-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide(04-41)

The title compound was prepared from Example 01-34 and m-fluoroanilineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 16mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (12%yield). ¹H NMR (D6-DMSO) δ 1.46-1.53 (m, 3H), 1.60-1.70 (m, 5H),1.72-1.79 (m, 2H), 1.90-2.07 (m, 2H), 2.09-2.13 (m, 2H), 2.50-2.58 (m,2H), 3.45-3.60 (m, 1H), 6.83-6.93 (m, 2H), 7.30-7.36 (m, 2H), 7.64 (d,J=12.0 Hz, 1H), 9.98 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₁₉H₂₄FN₂O₂;C₁₉H₂₃FN₂NaO₂; C₃₈H₄₇F₂N₄O₄; C₃₈H₄₆F₂N₄NaO₄ 331.18; 353.16; 661.36;683.34 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 331.26; 353.23; 661.45;683.44.

Example 04-42 Preparation of(1S,4S)—N-(4-chlorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide(04-42)

The title compound was prepared from Example 01-34 and p-chloroanilineaccording to the procedure of Example 04-13; 0.42 mmol scale yielded 13mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (9%yield). ¹H NMR (D6-DMSO) δ 1.46-1.54 (m, 3H), 1.59-1.69 (m, 5H),1.72-1.79 (m, 2H), 2.00-2.07 (m, 2H), 2.09-2.13 (m, 2H), 2.50-2.54 (m,2H), 3.40-3.58 (m, 1H), 6.83-6.92 (m, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.65(d, J=8.6 Hz, 2H), 9.90 (s, 1H). LCMS t=5.7 min, m/z Calcd forC₁₉H₂₄ClN₂O₂; C₁₉H₂₃ClN₂NaO₂; C₃₈H₄₆Cl₂N₄NaO₄ 347.15; 369.13; 715.28[M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 347.22; 369.20; 715.39.

Example 04-43 Preparation of2-chloro-N-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-43)

The title compound was prepared from Example 01-10 and cyclohexylamineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 1mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (1%yield). ¹H NMR (D6-DMSO) δ 1.10-1.18 (m, 2H), 1.27-1.33 (m, 4H), 1.58(s, 3H), 1.70-1.73 (m, 2H), 1.81-1.83 (m, 2H), 2.23-2.25 (m, 2H),2.72-2.75 (m, 2H), 3.32-3.70 (m, 1H), 7.22 (dd, J=8.2, 1.7 Hz, 1H), 7.32(d, J=1.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.95(s, 1H). LCMS t=5.7 min, m/z Calcd for C₁₉H₂₄ClN₂O₂; C₁₉H₂₃ClN₂NaO₂;C₃₆H₄₇Cl₂N₄O₄; C₃₆H₄₇Cl₂N₄NaO₄ 347.15; 369.13; 693.30; 715.28 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 347.23; 369.20; 693.41; 715.41.

Example 04-44 Preparation of2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)-benzamide(04-44)

The title compound was prepared from Example 01-10 and1-aminonaphthalene according to the procedure of Example 04-13; 0.38mmol scale yielded 40 mg after chromatography (ESS=H:E (1:19)) and EtOActrituration (27% yield). ¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.27-2.29 (m,2H), 2.80-2.82 (m, 2H), 7.35 (d, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.54-7.59(m, 3H), 7.70-7.74 (m, 2H), 7.85 (d, J=8.1 Hz, 1H), 7.97 (d, J=8.6 Hz,1H), 8.16 (d, J=9.0 Hz, 1H), 9.19 (s, 1H), 10.50 (s, 1H). LCMS t=5.8min, m/z Calcd for C₂₃H₂₀ClN₂O₂; C₂₃H₁₉ClN₂NaO₂; C₄₆H₃₉Cl₂N₄O₄;C₄₆H₃₈Cl₂N₄NaO₄ 391.12; 413.10; 781.23; 803.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 391.19; 413.17; 781.39; 803.38.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 452-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- H H Hyl)amino)-N-phenylbenzamide 462-Chloro-N-(2-methoxyphenyl)-4-((2-methyl-3- OCH₃ H Hoxocyclopent-1-en-1-yl)amino)benzamide 472-Chloro-N-(3-methoxyphenyl)-4-((2-methyl-3- H OCH₃ Hoxocyclopent-1-en-1-yl)amino)benzamide 482-Chloro-N-(4-methoxyphenyl)-4-((2-methyl-3- H H OCH₃oxocyclopent-1-en-1-yl)amino)benzamide 492-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- CH₃ H Hyl)amino)-N-(o-tolyl)benzamide 502-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- H CH₃ Hyl)amino)-N-(m-tolyl)benzamide 512-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1- H H CH₃yl)amino)-N-(p-tolyl)benzamide 522-Chloro-N-(3-fluorophenyl)-4-((2-methyl-3- H F Hoxocyclopent-1-en-1-yl)amino)benzamide

Example 04-45 Preparation of2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide(04-45)

The title compound was prepared from Example 01-10 and aniline accordingto the procedure of Example 04-13; 0.38 mmol scale yielded 17 mg afterchromatography (ESS=EtOAc) and EtOAc trituration (13% yield). ¹H NMR(D6-DMSO) δ 1.61 (s, 3H), 2.25-2.28 (m, 2H), 2.78-2.80 (m, 2H), 7.10 (t,J=7.4 Hz, 1H), 7.30 (dd, J=8.3, 1.6 Hz, 1H), 7.35 (t, J=7.8 Hz, 2H),7.41 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.72 (d, J=7.9 Hz, 2H), 9.16 (s,1H), 10.43 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₁₉H₁₈ClN₂O₂;C₁₉H₁₇ClN₂NaO₂; C₃₈H₃₅Cl₂N₄O₄; C₃₈H₃₄Cl₂N₄NaO₄ 341.11; 363.09; 681.20;703.19 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 341.18; 363.16; 681.31;703.31.

Example 04-46 Preparation of2-chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-46)

The title compound was prepared from Example 01-10 and o-anisidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 45mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (30%yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.79-2.80(m, 2H), 3.83 (s, 3H), 6.97 (t, J=6.9 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H),7.16 (t, J=7.5 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 7.39 (s, 1H), 7.59 (d,J=7.6 Hz, 1H), 7.96 (d, J=6.6 Hz, 1H), 9.16 (s, 1H), 9.51 (s, 1H). LCMSt=5.8 min, m/z Calcd for C₂₀H₂₀ClN₂O₃; C₂₀H₁₉ClN₂NaO₃; C₄₀H₃₉Cl₂N₄O₆;C₄₀H₃₈Cl₂N₄NaO₆ 371.11; 393.10; 741.22; 763.21 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 371.18; 393.16; 741.36; 763.35.

Example 04-47 Preparation of2-chloro-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-47)

The title compound was prepared from Example 01-10 and m-anisidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 47mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (34%yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.25-2.28 (m, 2H), 2.78-2.79(m, 2H), 3.75 (s, 3H), 6.69 (d, J=7.0 Hz, 1H), 7.22-7.31 (m, 3H),7.40-7.42 (m, 2H), 7.54 (d, J=8.3 Hz, 1H), 9.16 (s, 1H), 10.41 (s, 1H).LCMS t=5.7 min, m/z Calcd for C₂₀H₂₀ClN₂O₃; C₂₀H₁₉ClN₂NaO₃;C₄₀H₃₉Cl₂N₄O₆; C₄₀H₃₈Cl₂N₄NaO₆ 371.11; 393.10; 741.22; 763.21 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 371.18; 393.16; 741.36; 763.35.

Example 04-48 Preparation of2-chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-48)

The title compound was prepared from Example 01-10 and p-anisidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 17mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (12%yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.77-2.79(m, 2H), 3.74 (s, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.2 Hz, 1H),7.40 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 9.15 (s,1H), 10.29 (s, 1H). LCMS t=5.6 min, m/z Calcd for C₂₀H₂₀ClN₂O₃;C₂₀H₁₉ClN₂NaO₃; C₄₀H₃₉Cl₂N₄O₆; C₄₀H₃₈Cl₂N₄NaO₆ 371.11; 393.10; 741.22;763.21 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 371.18; 393.16; 741.35;763.34.

Example 04-49 Preparation of2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-49)

The title compound was prepared from Example 01-10 and o-toluidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 25mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (19%yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.29 (m, 5H), 2.78-2.80(m, 2H), 7.15 (t, J=7.1 Hz, 1H), 7.21-7.23 (m, 1H), 7.26 (d, J=7.1 Hz,1H), 7.31 (d, J=7.9 Hz, 1H), 7.40-7.43 (m, 2H), 7.59 (d, J=8.1 Hz, 1H),9.16 (s, 1H), 9.91 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₂₀H₂₀ClN₂O₂;C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄ 355.12; 377.10; 709.23;731.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.19; 377.17; 709.34;731.34.

Example 04-50 Preparation of2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide(04-50)

The title compound was prepared from Example 01-10 and m-toluidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 36mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (27%yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.30 (s,3H), 2.78-2.79 (m, 2H), 6.92 (d, J=7.3 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H),7.30 (d, J=8.2 Hz, 1H), 7.40 (s, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.53 (d,J=8.2 Hz, 1H), 9.16 (s, 1H), 10.36 (s, 1H). LCMS t=5.8 min, m/z Calcdfor C₂₀H₂₀ClN₂O₂; C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄ 355.12;377.10; 709.23; 731.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.19;377.17; 709.35; 731.34.

Example 04-51 Preparation of2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide(04-51)

The title compound was prepared from Example 01-10 and p-toluidineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 21mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (16%yield). ¹H NMR (D6-DMSO) δ 1.61 (2, 3H), 2.27-2.29 (m, 5H), 2.77-2.78(m, 2H), 7.15 (d, J=7.8 Hz, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.40 (s, 1H),7.53 (d, J=8.3 Hz, 1H), 7.60 (d, J=7.9 Hz, 2H), 9.16 (s, 1H), 10.34 (s,1H). LCMS t=5.8 min, m/z Calcd for C₂₀H₂₀ClN₂O₂; C₂₀H₁₉ClN₂NaO₂;C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄ 355.12; 377.10; 709.23; 731.22 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.19; 377.17; 709.34; 731.33.

Example 04-52 Preparation of2-chloro-N-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-52)

The title compound was prepared from Example 01-10 and m-fluoroanilineaccording to the procedure of Example 04-13; 0.38 mmol scale yielded 25mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (18%yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.78-2.80(m, 2H), 6.94 (d, J=8.2 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.36-7.42 (m,2H), 7.46 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.68 (d, J=11.3 Hz,1H), 9.17 (s, 1H), 10.65 (s, 1H). LCMS t=5.8 min, m/z Calcd forC₁₉H₁₇ClFN₂O₂; C₁₉H₁₆ClFN₂NaO₂; C₃₈H₃₃Cl₂F₂N₄O₄; C₃₈H₃₂Cl₂F₂N₄NaO₄359.10; 381.08; 717.18; 739.17 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found359.16; 381.14; 717.30; 739.29.

Example 04-53 Preparation of3-methoxy-N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-53)

The title compound was prepared from Example 01-12 and methylamineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 25mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (23%yield). ¹H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.16-2.19 (m, 2H), 2.48-2.51(m, 2H), 2.79 (d, J=4.5 Hz, 1H), 3.87 (s, 3H), 7.25 (d, J=8.1 Hz, 1H),7.43 (dd, J=8.1, 1.4 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 8.42-8.44 (m, 1H),8.51 (s, 1H). LCMS t=4.9 min, m/z Calcd for C₁₅H₁₉N₂O₃; C₁₅H₈N₂NaO₃;C₃₀H₃₆N₄NaO₆ 275.14; 297.12; 571.25 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found275.23; 297.21; 571.42.

Example 04-54 Preparation ofN-cyclohexyl-3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-54)

The title compound was prepared from Example 01-12 and cyclohexylamineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 52mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (38%yield). ¹H NMR (D6-DMSO) δ 1.20-1.28 (m, 1H), 1.32-1.35 (m, 4H), 1.51(s, 3H), 1.62 (d, J=11.9 Hz, 1H), 1.75 (s, 2H), 1.82 (s, 2H), 2.16-2.19(m, 2H), 2.47-2.50 (m, 2H), 3.75-3.78 (m, 1H), 3.88 (s, 3H), 7.24 (d,J=8.1 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 8.19 (d, J=7.9 Hz,1H), 8.53 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₂₀H₂₇N₂O₃;C₂₀H₂₆N₂NaO₃; C₄₀H₅₂N₄NaO₆ 343.20; 365.18; 707.38 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 343.27; 365.25; 707.55.

Example 04-55 Preparation of3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)-benzamide(04-55)

The title compound was prepared from Example 01-12 and1-aminonaphthalene according to the procedure of Example 04-13; 0.40mmol scale yielded 41 mg after chromatography (ESS=H:E (1:19)) and EtOActrituration (27% yield). ¹H NMR (D6-DMSO) δ 1.55 (s, 3H), 2.21-2.23 (m,2H), 2.56-2.58 (m, 2H), 3.95 (s, 3H), 7.36 (d, J=8.1 Hz, 1H), 7.55-7.60(m, 4H), 7.73 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.88 (d, J=7.7 Hz, 1H),7.98-8.00 (m, 2H), 8.60 (s, 1H), 10.43 (s, 1H). LCMS t=5.8 min, m/zCalcd for C₂₄H₂₃N₂O₃; C₂₄H₂₂N₂NaO₃; C₄₈H₄₅N₄O₆; C₄₈H₄₄N₄NaO₆ 387.17;409.15; 773.33; 795.32 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 387.24;409.22; 773.48; 795.47.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 563-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1- H H Hyl)amino)-N-phenylbenzamide 573-Methoxy-N-(2-methoxyphenyl)-4-((2-methyl-3- OCH₃ H Hoxocyclopent-1-en-1-yl)amino)benzamide 583-Methoxy-N-(3-methoxyphenyl)-4-((2-methyl-3- H OCH₃ Hoxocyclopent-1-en-1-yl)amino)benzamide 593-Methoxy-N-(4-methoxyphenyl)-4-((2-methyl-3- H H OCH₃oxocyclopent-1-en-1-yl)amino)benzamide 603-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1- CH₃ H Hyl)amino)-N-(o-tolyl)benzamide 613-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1- H CH₃ Hyl)amino)-N-(m-tolyl)benzamide 623-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1- H H CH₃yl)amino)-N-(p-tolyl)benzamide 63N-(3-Fluorophenyl)-3-methoxy-4-((2-methyl-3- H F Hoxocyclopent-1-en-1-yl)amino)benzamide 64N-(4-Chlorophenyl)-3-methoxy-4-((2-methyl-3- H H Cloxocyclopent-1-en-1-yl)amino)benzamide

Example 04-56 Preparation of3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide(04-56)

The title compound was prepared from Example 01-12 and aniline accordingto the procedure of Example 04-13; 0.40 mmol scale yielded 35 mg afterchromatography (ESS=H:E (1:19)) and EtOAc trituration (26% yield). ¹HNMR (D6-DMSO) δ 1.53 (s, 3H), 2.19-2.22 (m, 2H), 2.53-2.55 (m, 2H), 3.93(s, 3H), 7.11 (t, J=8.1 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.36 (t, J=7.8Hz, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.76 (d, J=7.8Hz, 2H), 8.57 (s, 1H), 10.21 (s, 1H). LCMS t=5.6 min, m/z Calcd forC₂₀H₂₁N₂O₃; C₂₀H₂₀N₂NaO₃; C₄₀H₄₁N₄O₆; C₄₀H₄₀N₄NaO₆ 337.16; 359.14;673.30; 695.28 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 337.23; 359.21;673.41; 695.41.

Example 04-57 Preparation of3-methoxy-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-57)

The title compound was prepared from Example 01-12 and o-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 30mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (20%yield). ¹H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.53-2.55(m, 2H), 3.84 (s, 3H), 3.92 (s, 3H), 6.98 (t, J=7.5 Hz, 1H), 7.10 (d,J=8.1 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.58 (d,J=7.9 Hz, 1H), 7.64 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.55 (s, 1H), 9.46(s, 1H). LCMS t=5.9 min, m/z Calcd for C₂₁H₂₃N₂O₄; C₂₁H₂₂N₂NaO₄;C₄₂H₄₅N₄O₈; C₄₂H₄₄N₄NaO₈ 367.17; 389.15; 733.32; 755.31 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 367.24; 389.22; 733.46; 755.46.

Example 04-58 Preparation of3-methoxy-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-58)

The title compound was prepared from Example 01-12 and m-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 53mg after chromatography (ESS=EtOAc) and EtOAc trituration (36% yield).¹H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.19-2.22 (m, 2H), 2.53-2.55 (m, 2H),3.76 (s, 3H), 3.93 (s, 3H), 6.69 (dd, J=8.1, 2.0 Hz, 1H), 7.26 (t, J=8.1Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.47 (s, 1H),7.58-7.61 (m, 2H), 8.57 (s, 1H), 10.18 (s, 1H). LCMS t=5.7 min, m/zCalcd for C₂₁H₂₃N₂O₄; C₂₁H₂₂N₂NaO₄; C₄₂H₄₅N₄O₈; C₄₂H₄₄N₄NaO₈ 367.17;389.15; 733.32; 755.31 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 367.24;389.22; 733.46; 755.45.

Example 04-59 Preparation of3-methoxy-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-59)

The title compound was prepared from Example 01-12 and p-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 55mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (38%yield). ¹H NMR (D6-DMSO) δ1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.52-2.53 (m,2H), 3.75 (s, 3H), 3.92 (s, 2H), 6.94 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.66 (d, J=8.7 Hz, 2H),8.56 (s, 1H), 10.10 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.3, 25.5, 32.8, 55.2,55.9, 109.8, 110.9, 113.7, 119.9, 122.2, 124.7, 131.1, 132.1, 132.3,152.4, 155.6, 164.4, 169.6, 202.1. LCMS t=5.6 min, m/z Calcd forC₂₁H₂₃N₂O₄; C₂₁H₂₂N₂NaO₄; C₄₂H₄₅N₄O₈; C₄₂H₄₄N₄NaO₈ 367.17; 389.15;733.32; 755.31 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 367.23; 389.21;733.44; 755.43.

Example 04-60 Preparation of3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-60)

The title compound was prepared from Example 01-12 and o-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 60mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (43%yield). ¹H NMR (D6-DMSO) δ 1.54 (s, 3H), 2.20-2.22 (m, 2H), 2.24 (s,3H), 2.53-2.55 (m, 2H), 3.92 (s, 3H), 7.18 (t, J=7.1 Hz, 1H), 7.23 (t,J=7.2 Hz, 1H), 7.29 (d, J=7.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.61 (d,J=8.0 Hz, 1H), 7.66 (s, 1H), 8.58 (s, 1H), 9.89 (s, 1H). LCMS t=5.7 min,m/z Calcd for C₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃; C₄₂H₄₅N₄O₆; C₄₂H₄₄N₄NaO₆ 351.17;373.15; 701.33; 723.32 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 351.24;373.22; 701.45; 723.44.

Example 04-61 Preparation of3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide(04-61)

The title compound was prepared from Example 01-12 and m-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 47mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (34%yield). ¹H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.32, (s,3H), 2.53-2.55 (m, 2H), 3.93 (m, 3H), 6.93 (d, J=7.3 Hz, 1H), 7.24 (t,J=7.7 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.56-7.62 (m, 4H), 8.57 (s, 1H),10.13 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.3, 21.2, 25.5, 32.8, 55.9, 109.9,110.93, 117.7, 120.1, 121.1, 124.4, 124.6, 128.4, 131.2, 132.2, 137.7,139.0, 152.4, 164.7, 169.6, 202.1. LCMS t=5.8 min, m/z Calcd forC₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃; C₄₂H₄₅N₄O₆; C₄₂H₄₄N₄NaO₆ 351.17; 373.15;701.33; 723.32 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 351.24; 373.22;701.44; 723.43.

Example 04-62 Preparation of3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide(04-62)

The title compound was prepared from Example 01-12 and p-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 45mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (32%yield). ¹H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.29 (s,3H), 2.53-2.55 (m, 2H), 3.92 (s, 3H), 7.16 (d, J=8.0 Hz, 2H), 7.32 (d,J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.64 (d, J=8.0 Hz,2H), 8.57 (s, 1H), 10.14 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.3, 20.5, 25.5,32.8, 55.9, 109.9, 110.9, 120.0, 120.6, 124.7, 129.0, 131.2, 132.3,132.7, 136.6, 152.4, 164.6, 169.6, 202.1. LCMS t=5.8 min, m/z Calcd forC₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃; C₄₂H₄₅N₄O₆; C₄₂H₄₄N₄NaO₆ 351.17; 373.15;701.33; 723.32 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 351.24; 373.22;701.44; 723.43.

Example 04-63 Preparation ofN-(3-fluorophenyl)-3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-63)

The title compound was prepared from Example 01-12 and m-fluoroanilineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 51mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (36%yield). ¹H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.40-2.56(m, 2H), 3.93 (s, 3H), 6.94 (t, J=7.7 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H),7.40 (dd, J=15.2, 7.9 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.59 (d, J=11.7Hz, 1H), 8.58 (s, 1H), 10.39 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.4, 25.6,32.8, 55.9, 107.0 (J_(CF)=26.2 Hz), 110.1 (J_(CF)=15.7 Hz), 111.0,116.1, 120.1, 124.5, 130.2 (J_(CF)=9.1 Hz), 131.6 (J_(CF)=19.6 Hz),141.0, 152.2, 162.1 (J_(CF)=241.2 Hz), 165.1, 169.4, 202.2. LCMS t=5.8min, m/z Calcd for C₂₀H₂₀FN₂O₃; C₂₀H₁₉FN₂NaO₃; C₄₀H₃₉F₂N₄O₆;C₄₀H₃₈F₂N₄NaO₆ 355.15; 377.13; 709.28; 731.27 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 355.21; 377.19; 709.39; 731.38.

Example 04-64 Preparation ofN-(4-chlorophenyl)-3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-64)

The title compound was prepared from Example 01-12 and p-chloroanilineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 52mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (35%yield). ¹H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.53-2.55(m, 2H), 3.93 (s, 3H), 7.33 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H),7.58-7.61 (m, 3H), 7.81 (d, J=8.6 Hz, 2H), 8.57 (s, 1H), 10.33 (s, 1H).¹³C NMR (D6-DMSO) δ 7.4, 25.6, 32.8, 55.9, 110.0, 111.1, 120.1, 122.0,124.5, 127.3, 128.5, 131.5, 131.8, 138.1, 152.3, 164.9, 169.5, 202.1.LCMS t=5.9 min, m/z Calcd for C₂₀H₂₀ClN₂O₃; C₂₀H₁₉ClN₂NaO₃;C₄₀H₃₉Cl₂N₄O₆; C₄₀H₃₈Cl₂N₄NaO₆ 371.12; 393.10; 741.22; 763.21 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 371.18; 393.16; 741.35; 763.34.

Example 04-65 Preparation of2-methoxy-N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-65)

The title compound was prepared from Example 02-03 and methylamineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 25mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (22%yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.23-2.26 (m, 2H), 2.78-2.80(m, 5H), 3.89 (s, 3H), 6.89 (dd, J=8.4, 1.7 Hz, 1H), 6.96 (d, J=1.6 Hz,1H), 7.78 (d, J=8.4 Hz, 1H), 8.03-8.05 (m, 2H), 9.08 (s, 1H). LCMS t=4.6min, m/z Calcd for C₁₅H₁₉N₂O₃; C₁₅H₁₈N₂NaO₃; C₃₀H₃₆N₄NaO₆ 275.14;297.12; 571.25 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 275.23; 297.21; 571.34.

Example 04-66 Preparation ofN-cyclohexyl-2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-66)

The title compound was prepared from Example 02-03 and cyclohexylamineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 90mg after chromatography (ESS=EtOAc) and EtOAc trituration (66% yield).¹H NMR (D6-DMSO) δ 1.18-1.28 (m, 1H), 1.30-1.35 (m, 4H), 1.56 (d, J=12.9Hz, 1H), 1.61 (s, 3H), 1.66-1.69 (m, 2H), 1.81-1.84 (m, 2H), 2.24-2.26(m, 2H), 2.78-2.80 (m, 2H), 3.77-3.79 (m, 1H), 3.90 (s, 3H), 6.90 (dd,J=8.4, 1.6 Hz, 1H), 6.97 (d, J=1.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.85(d, J=7.8 Hz, 1H), 8.53 (s, 1H). LCMS t=5.8 min, m/z Calcd forC₂₀H₂₇N₂O₃; C₂₀H₂₆N₂NaO₃; C₄₀H₅₃N₄O₆; C₄₀H₅₂N₄NaO₆ 343.20; 365.18;685.40; 707.38 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 343.28; 365.26;685.50; 707.52.

Example 04-67 Preparation of2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide(04-67)

The title compound was prepared from Example 02-03 and1-aminonaphthalene according to the procedure of Example 04-13; 0.40mmol scale yielded 13 mg after chromatography (ESS=EtOAc) and EtOActrituration (8% yield). ¹H NMR (D6-DMSO) δ 1.65 (s, 3H), 2.28-2.30 (m,2H), 2.87-2.89 (m, 2H), 4.10 (s, 3H), 7.02 (d, J=8.1 Hz, 1H), 7.12 (s,1H), 7.55-7.60 (m, 2H), 7.64 (t, J=7.5 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H),7.92 (d, J=8.5 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.4 Hz, 2H),9.19 (s, 1H), 10.31 (s, 1H). LCMS t=6.0 min, m/z Calcd for C₂₄H₂₃N₂O₃;C₂₄H₂₂N₂NaO₃; C₄₈H₄₅N₄O₆; C₄₈H₄₄N₄NaO₆ 387.17; 409.15; 773.33 795.32[M+H; M+Na]; [2M+H]; [2M+Na]⁺, Found 387.24 409.22 773.49 795.47.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 682-Methoxy-4-((2-methyl-3-oxocyclopent-1-en- H H H1-yl)amino)-N-phenylbenzamide 692-Methoxy-N-(2-methoxyphenyl)-4-((2-methyl- OCH₃ H H3-oxocyclopent-1-en-1-yl)amino)benzamide 702-Methoxy-N-(3-methoxyphenyl)-4-((2-methyl- H OCH₃ H3-oxocyclopent-1-en-1-yl)amino)benzamide 712-Methoxy-N-(4-methoxyphenyl)-4-((2-methyl- H H OCH₃3-oxocyclopent-1-en-1-yl)amino)benzamide 722-Methoxy-4-((2-methyl-3-oxocyclopent-1-en- CH₃ H H1-yl)amino)-N-(o-tolyl)benzamide 732-Methoxy-4-((2-methyl-3-oxocyclopent-1-en- H CH₃ H1-yl)amino)-N-(m-tolyl)benzamide 742-Methoxy-4-((2-methyl-3-oxocyclopent-1-en- H H CH₃1-yl)amino)-N-(p-tolyl)benzamide 75N-(3-Fluorophenyl)-2-methoxy-4-((2-methyl-3- H F Hoxocyclopent-1-en-1-yl)amino)benzamide 76N-(4-Chlorophenyl)-2-methoxy-4-((2-methyl-3- H H Cloxocyclopent-1-en-1-yl)amino)benzamide

Example 04-68 Preparation of2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide(04-68)

The title compound was prepared from Example 02-03 and aniline accordingto the procedure of Example 04-13; 0.40 mmol scale yielded 52 mg afterchromatography (ESS=EtOAc) and EtOAc trituration (39% yield). ¹H NMR(D6-DMSO) δ 1.63 (s, 3H), 2.25-2.28 (m, 2H), 2.82-2.83 (m, 2H), 3.95 (s,3H), 6.95 (dd, J=8.4, 1.6 Hz, 1H), 7.03 (s, 1H), 7.08 (t, J=8.4 Hz, 1H),7.34 (t, J=7.8 Hz, 2H), 7.70-7.74 (m, 3H), 9.14 (s, 1H), 9.99 (s, 1H).LCMS t=5.8 min, m/z Calcd for C₂₀H₂₁N₂O₃; C₂₀H₂₀N₂NaO₃; C₄₀H₄₁N₄O₆;C₄₀H₄₀N₄NaO₆ 337.16; 359.14; 673.30; 695.28 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 337.23; 359.21; 673.42; 695.40.

Example 04-69 Preparation of2-methoxy-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-69)

The title compound was prepared from Example 02-03 and o-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 60mg after chromatography (ESS=MeOH (2%)) and EtOAc trituration (41%yield). ¹H NMR (D6-DMSO) δ 1.64 (s, 3H), 2.27-2.29 (m, 2H), 2.88-2.90(m, 2H), 3.96 (s, 3H), 4.08 (s, 3H), 6.96 (d, J=8.0 Hz, 1H), 7.02 (dd,J=8.6, 1.6 Hz, 1H), 7.06-7.10 (m, 3H), 8.04 (d, J=8.6 Hz, 1H), 8.47 (d,J=7.8 Hz, 1H), 9.19 (s, 1H), 10.57 (s, 1H). LCMS t=5.9 min, m/z Calcdfor C₂₁H₂₃N₂O₄; C₂₁H₂₂N₂NaO₄; C₄₂H₄₅N₄O₈; C₄₂H₄₄N₄NaO₈ 367.17; 389.15;733.32; 755.31 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 367.24; 389.21;733.45; 755.45.

Example 04-70 Preparation of2-methoxy-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-70)

The title compound was prepared from Example 02-03 and m-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 55mg after chromatography (ESS=EtOAc) and EtOAc trituration (38% yield).¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H),3.75 (s, 3H), 3.94 (s, 3H), 6.67 (d, J=8.3 Hz, 1H), 6.95 (d, J=8.3 Hz,1H), 7.02 (s, 1H), 7.21-7.28 (m, 2H), 7.45 (s, 1H), 7.69 (d, J=8.3 Hz,1H), 9.14 (s, 1H), 9.97 (s, 1H). LCMS t=5.8 min, m/z Calcd forC₂₁H₂₃N₂O₄; C₂₁H₂₂N₂NaO₄; C₄₂H₄₅N₄O₈; C₄₂H₄₄N₄NaO₈ 367.17; 389.15;733.32; 755.31 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 367.24; 389.22;733.45; 755.45.

Example 04-71 Preparation of2-methoxy-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-71)

The title compound was prepared from Example 02-03 and p-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 29mg after chromatography (ESS=EtOAc) and EtOAc trituration (20% yield).¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H),3.74 (s, 3H), 3.94 (s, 3H), 6.91 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.3 Hz,1H), 7.02 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.3 Hz, 1H), 9.13(s, 1H), 9.85 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.4, 26.1, 33.1, 55.2, 56.1,105.0, 111.7, 113.1, 113.8, 118.5, 121.4, 131.1, 132.2, 143.9, 155.4,157.4, 163.1, 168.3, 202.2. LCMS t=5.8 min, m/z Calcd for C₂₁H₂₃N₂O₄;C₂₁H₂₂N₂NaO₄; C₄₂H₄₅N₄O₈; C₄₂H₄₄N₄NaO₈ 367.17; 389.15; 733.32; 755.31[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 367.23; 389.21; 733.53;755.44.

Example 04-72 Preparation of2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-72)

The title compound was prepared from Example 02-03 and o-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 70mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (50%yield). ¹H NMR (D6-DMSO) δ 1.64 (s, 3H), 2.27-2.29 (m, 2H), 2.32 (s,3H), 2.86-2.88 (m, 2H), 4.03 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.04-7.09(m, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 7.95 (d, J=8.4Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 9.18 (s, 1H), 9.78 (s, 1H). ¹³C NMR(D6-DMSO) δ 7.5, 17.7, 26.2, 33.1, 56.5, 104.7, 112.2, 113.2, 116.4,122.2, 124.1, 126.3, 128.6, 130.3, 132.2, 136.9, 144.7, 157.7, 162.4,168.1, 202.4. LCMS t=5.9 min, m/z Calcd for C₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃;C₄₂H₄₅N₄O₆; C₄₂H₄₄N₄NaO₆ 351.17; 373.15; 701.33; 723.32 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 351.24; 373.22; 701.44; 723.43.

Example 04-73 Preparation of2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide(04-73)

The title compound was prepared from Example 02-03 and m-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 55mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (39%yield). ¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.30 (s,3H), 2.82-2.84 (m, 2H), 3.95 (s, 3H), 6.90 (d, J=6.9 Hz, 1H), 6.95 (d,J=8.1 Hz, 1H), 7.02 (s, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.53 (d, J=7.4 Hz,1H), 7.57 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 9.14 (s, 1H), 9.91 (s, 1H).¹³C NMR (D6-DMSO) δ 7.5, 21.2, 26.1, 33.1, 56.1, 105.0, 112.0, 113.1,117.0, 118.4, 120.3, 124.2, 128.5, 131.2, 137.9, 138.9, 144.1, 157.4,163.8, 168.3, 202.3. LCMS t=5.9 min, m/z Calcd for C₂₁H₂₃N₂O₃;C₂₁H₂₂N₂NaO₃; C₄₂H₄₅N₄O₆; C₄₂H₄₄N₄NaO₆ 351.17; 373.15; 701.33; 723.32[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 351.24; 373.22; 701.45;723.44.

Example 04-74 Preparation of2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide(04-74)

The title compound was prepared from Example 02-03 and p-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 30mg after chromatography (ESS=EtOAc) and EtOAc trituration (21% yield).¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.27-2.29 (m, 5H), 2.82-2.85 (m, 2H),3.94 (s, 3H), 6.95 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 7.14 (d, J=8.0 Hz,2H), 7.62 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.3 Hz, 1H), 9.13 (s, 1H), 9.90(s, 1H). ¹³C NMR (D6-DMSO) δ 7.4, 20.5, 26.1, 33.1, 56.1, 105.0, 111.7,113.1, 118.5, 119.8, 129.1, 131.2, 132.4, 136.5, 144.0, 157.4, 163.23,168.2, 202.3. LCMS t=5.9 min, m/z Calcd for C₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃;C₄₂H₄₅N₄O₆; C₄₂H₄₄N₄NaO₆ 351.17; 373.15; 701.33; 723.32 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 351.24; 373.22; 701.45; 723.44.

Example 04-75 Preparation ofN-(3-fluorophenyl)-2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-75)

The title compound was prepared from Example 02-03 and m-fluoroanilineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 75mg after chromatography (ESS=EtOAc) and EtOAc trituration (53% yield).¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H),2.94 (s, 3H), 6.91 (d, J=7.7 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 7.03 (s,1H), 7.37 (dd, J=15.3, 7.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.69 (d,J=8.3 Hz, 1H), 7.74 (d, J=11.5 Hz, 1H), 9.15 (s, 1H), 10.16 (s, 1H). ¹³CNMR (D6-DMSO) δ 7.5, 26.1, 33.1, 56.1, 104.9, 106.5 (J_(CF)=26.2 Hz),109.8 (J_(CF)=20.8 Hz), 111.9, 113.0, 115.6, 118.3, 130.3 (J_(CF)=9.2Hz), 131.1, 140.7 (J_(CF)=11.4 Hz), 144.3, 157.5, 163.5 (J_(CF)=241.3Hz), 164.0, 168.2, 202.3. LCMS t=5.9 min, m/z Calcd for C₂₀H₂₀FN₂O₃;C₂₀H₁₉FN₂NaO₃; C₄₀H₃₉F₂N₄O₆; C₄₀H₃₈F₂N₄NaO₆ 355.15; 377.13; 709.28;731.27 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.22; 358.22; 709.40;731.39.

Example 04-76 Preparation ofN-(4-chlorophenyl)-2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-76)

The title compound was prepared from Example 02-03 and p-chloroanilineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 70mg after chromatography (ESS=EtOAc) and EtOAc trituration (47% yield).¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H),3.93 (s, 3H), 6.95 (d, J=8.3 Hz, 1H), 7.02 (s, 1H), 7.39 (d, J=8.5 Hz,2H), 7.68 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 9.14 (s, 1H), 10.10(s, 1H). ¹³C NMR (D6-DMSO) δ 7.5, 26.1, 33.1, 56.1, 104.9, 111.9, 113.1,118.4, 121.4, 127.0, 128.6, 131.1, 138.0, 144.2, 157.4, 163.8, 168.3,202.3. LCMS t=6.0 min, m/z Calcd for C₂₀H₂₀ClN₂O₃; C₂₀H₁₉ClN₂NaO₃;C₄₀H₃₉Cl₂N₄O₆; C₄₀H₃₈Cl₂N₄NaO₆ 371.12; 393.10; 741.22; 763.21 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 371.18; 393.16; 741.35; 763.34.

Example 04-77 Preparation ofN,3-dimethyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-77)

The title compound was prepared from Example 01-14 and methylamineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 35mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (34%yield). ¹H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.16-2.19 (m, 2H), 2.28 (s,3H), 2.41-2.43 (m, 2H), 2.77 (d, J=4.4 Hz, 3H), 7.23 (d, J=8.1 Hz, 1H),7.66 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 8.38-8.39 (m, 1H), 8.69 (s, 1H).LCMS t=4.9 min, m/z Calcd for C₁₅H₁₉N₂O₂; C₁₅H₁₈N₂NaO₂; C₃₀H₃₇N₄O₄;C₃₀H₃₆N₄NaO₄ 259.14; 281.13; 517.28; 539.26 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 259.24; 281.22; 517.35; 539.42.

Example 04-78 Preparation ofN-cyclohexyl-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-78)

The title compound was prepared from Example 01-14 and cyclohexylamineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 25mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (19%yield). ¹H NMR (D6-DMSO) δ 1.10-1.18 (m, 1H), 1.23-1.34 (m, 4H), 1.44(s, 3H), 1.61 (d, J=12.4 Hz, 1H), 1.73 (s, 2H), 1.80 (s, 2H), 2.16-2.19(m, 2H), 2.28 (s, 3H), 2.40-2.42 (m, 2H), 3.75 (s, 1H), 7.21 (d, J=8.2Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 8.15 (d, J=7.8 Hz, 1H),8.70 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₂₀H₂₇N₂O₂; C₂₀H₂₆N₂NaO₂;C₄₀H₅₃N₄O₄; C₄₀H₅₂N₄NaO₄ 327.21; 349.19; 653.41; 675.39 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 327.28; 349.26; 653.50; 675.54.

Example 04-79 Preparation of3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide(04-79)

The title compound was prepared from Example 01-14 and1-aminonaphthalene according to the procedure of Example 04-13; 0.40mmol scale yielded 35 mg after chromatography (ESS=H:E (1:19)) and EtOActrituration (24% yield). ¹H NMR (D6-DMSO) δ 1.50 (s, 3H), 2.21-2.23 (m,3H), 2.36 (s, 3H), 2.48-2.50 (m, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.54-7.60(m, 4H), 7.87 (d, J=7.9 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.97-8.02 (m,3H), 8.78 (s, 1H), 10.40 (s, 1H). LCMS t=5.8 min, m/z Calcd forC₂₄H₂₃N₂O₂; C₂₄H₂₂N₂NaO₂; C₄₈H₄₅N₄O₄; C₄₈H₄₄N₄NaO₄ 371.18; 393.16;741.34; 763.33 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 371.24; 393.22;741.47; 763.46.

EXAMPLE 04-# TITLE COMPOUND NAME R¹ R² R³ 803-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1- H H Hyl)amino)-N-phenylbenzamide 81N-(2-Methoxyphenyl)-3-methyl-4-((2-methyl- OCH₃ H H3-oxocyclopent-1-en-1-yl)amino)benzamide 82N-(3-Methoxyphenyl)-3-methyl-4-((2-methyl- H OCH₃ H3-oxocyclopent-1-en-1-yl)amino)benzamide 83N-(4-Methoxyphenyl)-3-methyl-4-((2-methyl- H H OCH₃3-oxocyclopent-1-en-1-yl)amino)benzamide 843-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1- CH₃ H Hyl)amino)-N-(o-tolyl)benzamide 853-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1- H CH₃ Hyl)amino)-N-(m-tolyl)benzamide 863-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1- H H CH₃yl)amino)-N-(p-tolyl)benzamide 87N-(3-Fluorophenyl)-3-methyl-4-((2-methyl-3- H F Hoxocyclopent-1-en-1-yl)amino)benzamide 88N-(4-Chlorophenyl)-3-methyl-4-((2-methyl-3- H H Cloxocyclopent-1-en-1-yl)amino)benzamide

Example 04-80 Preparation of3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide(04-80)

The title compound was prepared from Example 01-14 and aniline accordingto the procedure of Example 04-13; 0.40 mmol scale yielded 35 mg afterchromatography (ESS=H:E (1:19)) and EtOAc trituration (27% yield). ¹HNMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.21 (m, 2H), 2.33 (s, 3H), 2.45-2.47(m, 2H), 7.10 (t, J=7.3 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.35 (t, J=7.7Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.87 (s, 1H),8.74 (s, 1H), 10.20 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₂₀H₂₁N₂O₂;C₂₀H₂₀N₂NaO₂; C₄₀H₄₁N₄O₄; C₄₀H₄₀N₄NaO₄ 321.16; 343.14; 641.31; 663.29[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 321.24; 343.21; 641.41;663.41.

Example 04-81 Preparation ofN-(2-methoxyphenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-81)

The title compound was prepared from Example 01-14 and o-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 30mg after chromatography (ESS=EtOAc) and EtOAc trituration (21% yield).¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.22 (m, 2H), 2.33 (s, 3H),2.45-2.47 (m, 2H), 3.84 (s, 3H), 6.97 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.1Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.7Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.89 (s, 1H), 8.74 (s, 1H), 9.40 (s,1H). LCMS t=5.8 min, m/z Calcd for C₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃; C₄₂H₄₅N₄O₆;C₄₂H₄₄N₄NaO₆ 351.17; 373.15; 701.33; 723.32 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 351.24; 373.22; 701.45; 723.48.

Example 04-82 Preparation ofN-(3-methoxyphenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-82)

The title compound was prepared from Example 01-14 and m-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 31mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (22%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.22 (m, 2H), 2.33 (s,3H), 2.45-2.47 (m, 2H), 3.76 (s, 3H), 6.68 (d, J=8.2 Hz, 1H), 7.25 (t,J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.46 (s,1H), 7.79 (d, J=8.1 Hz, 1H), 7.86 (s, 1H), 8.74 (s, 1H), 10.17 (s, 1H).LCMS t=5.7 min, m/z Calcd for C₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃; C₄₂H₄₅N₄O₆;C₄₂H₄₄N₄NaO₆ 351.17; 373.15; 701.33; 723.32 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 351.24; 373.22; 701.45; 723.44.

Example 04-83 Preparation ofN-(4-methoxyphenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-83)

The title compound was prepared from Example 01-14 and p-anisidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 20mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (14%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.22 (m, 2H), 2.33 (s,3H), 2.44-2.46 (m, 2H), 2.75 (s, 3H), 6.93 (d, J=8.7 Hz, 2H), 7.29 (d,J=8.1 Hz, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.86 (s,1H), 8.74 (s, 1H), 10.09 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.6, 17.7, 25.6,32.7, 55.2, 108.9, 113.7, 121.9, 125.7, 126.1, 129.8, 132.1, 132.3,133.5, 140.9, 155.5, 164.6, 169.7, 202.2. LCMS t=5.6 min, m/z Calcd forC₂₁H₂₃N₂O₃; C₂₁H₂₂N₂NaO₃; C₄₂H₄₅N₄O₆; C₄₂H₄₄N₄NaO₆ 351.17; 373.15;701.33; 723.32 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 351.24; 373.22;701.45; 723.43.

Example 04-84 Preparation of3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-84)

The title compound was prepared from Example 01-14 and o-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 28mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (21%yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.19-2.21 (m, 2H), 2.24 (s,3H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 7.17 (d, J=7.3 Hz, 1H), 7.22 (d,J=7.4 Hz, 1H), 7.26-7.34 (m, 3H), 7.83 (d, J=8.1 Hz, 1H), 7.90 (s, 1H),8.75 (s, 1H), 9.85 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.6, 17.8, 18.0, 25.6,32.7, 109.0, 125.8, 126.0, 126.2, 126.6, 130.0, 130.3, 131.6, 133.6,133.8, 136.5, 141.0, 164.8, 169.7, 202.2. LCMS t=5.6 min, m/z Calcd forC₂₁H₂₃N₂O₂; C₂₁H₂₂N₂NaO₂; C₄₂H₄₅N₄O₄; C₄₂H₄₄N₄NaO₄ 335.18; 357.16;669.34; 691.33 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 335.28; 357.23;669.45; 691.43.

Example 04-85 Preparation of3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide(04-85)

The title compound was prepared from Example 01-14 and m-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 22mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (16%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.21 (m, 2H), 2.31 (s,3H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 6.92 (d, J=7.4 Hz, 1H), 7.22 (d,J=7.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.61 (s,1H), 7.79 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 8.74 (s, 1H), 10.12 (s, 1H).LCMS t=5.8 min, m/z Calcd for C₂₁H₂₃N₂O₂; C₂₁H₂₂N₂NaO₂; C₄₂H₄₅N₄O₄;C₄₂H₄₄N₄NaO₄ 335.18; 357.16; 669.34; 691.33 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 335.26; 357.23; 669.44; 691.43.

Example 04-86 Preparation of3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide(04-86)

The title compound was prepared from Example 01-14 and p-toluidineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 35mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (26%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.21 (m, 2H), 2.28 (s,3H), 2.33 (s, 3H), 2.44-2.46 (m, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.29 (d,J=8.1 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.86 (s,1H), 8.74 (s, 1H), 10.12 (s, 1H). LCMS t=5.8 min, m/z Calcd forC₂₁H₂₃N₂O₂; C₂₁H₂₂N₂NaO₂; C₄₂H₄₅N₄O₄; C₄₂H₄₄N₄NaO₄ 335.18; 357.16;669.34; 691.33 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 335.25; 357.23;669.44; 691.43.

Example 04-87 Preparation ofN-(3-fluorophenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-87)

The title compound was prepared from Example 01-14 and m-fluoroanilineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 30mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (22%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.22 (m, 2H), 2.34 (s,3H), 2.46-2.48 (m, 2H), 6.93 (t, J=8.3 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H),7.39 (dd, J=15.4, 7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.75 (d, J=11.7Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 8.75 (s, 1H), 10.39 (s,1H). ¹³C NMR (D6-DMSO) δ 7.6, 17.7, 25.6, 32.7, 106.9 (J_(CF)=26.2 Hz),109.2, 110.0 (J_(CF)=20.8 Hz), 115.9, 125.9 (J_(CF)=25.8 Hz), 130.1(J_(CF)=38.9 Hz), 131.6, 133.5, 141.0, 141.3, 162.1 (J_(CF)=240.7.3 Hz),165.3, 169.6, 202.2. LCMS t=5.7 min, m/z Calcd for C₂₀H₂₀FN₂O₂;C₂₀H₁₉FN₂NaO₂; C₄₀H₃₉F₂N₄O₄; C₄₀H₃₈F₂N₄NaO₄ 339.15; 361.13; 677.29;699.28 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 339.25; 361.20; 677.40;600.39.

Example 04-88 Preparation ofN-(4-chlorophenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide(04-88)

The title compound was prepared from Example 01-14 and p-chloroanilineaccording to the procedure of Example 04-13; 0.40 mmol scale yielded 25mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (18%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.22 (m, 3H), 2.33 (s,3H), 2.45-2.47 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.7 Hz, 2H),7.79-7.82 (m, 3H), 7.86 (s, 1H), 8.75 (s, 1H), 10.33 (s, 1H). ¹³C NMR(D6-DMSO) δ 7.6, 17.7 25.6, 32.7, 109.1, 121.8, 125.9, 126.1, 127.2,128.5, 130.0, 131.7, 133.5, 138.2, 141.3, 165.1, 169.6, 202.2. LCMSt=5.9 min, m/z Calcd for C₂₀H₂₀ClN₂O₂; C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄;C₄₀H₃₈Cl₂N₄NaO₄ 355.12; 377.10; 709.23; 731.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 355.19; 377.17; 709.35; 731.34.

Example 04-89 Preparation of4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-89)

The title compound was prepared from Example 01-25 and o-toluidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 50mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (28%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.23 (m, 5H), 2.45-2.47(m, 2H), 7.17-7.24 (m, 2H), 7.28 (d, J=7.3 Hz, 1H), 7.31 (d, J=7.6 Hz,1H), 7.74 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 9.03(s, 1H), 10.01 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.9, 18.3, 26.0, 33.1,110.0, 126.5, 126.7, 127.2, 128.0, 130.4, 130.8, 133.9, 134.2, 134.3,136.5, 137.2, 140.1, 160.5, 170.0, 202.9. LCMS t=4.8 min, m/z Calcd forC₂₀H₂₀ClN₂O₂; C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄ 355.12;377.10; 709.23; 731.22 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.12;377.11; 709.24; 731.22.

EXAM- PLE TITLE COMPOUND 04-# NAME R¹ R² 904-Chloro-N-(4-methoxyphenyl)-3-((2-methyl-3- H OCH₃oxocyclohex-1-en-1-yl)amino)benzamide 914-Chloro-3-((2-methyl-3-oxocyclohex-1-en-1- CH₃ Hyl)amino)-N-(o-tolyl)benzamide

Example 04-90 Preparation of4-chloro-N-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide(04-90)

The title compound was prepared from Example 01-36 and p-anisidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 90mg from solid precipitate (47% yield). ¹H NMR (D6-DMSO) δ 1.67 (s, 3H),1.77-1.80 (m, 2H), 2.19-2.22 (m, 2H), 2.24-2.27 (m, 2H), 3.75 (s, 3H),6.93 (d, J=9.0 Hz, 2H), 7.66 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.1 Hz, 1H),7.86-7.89 (m, 2H), 8.11 (s, 1H), 10.19 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.5,21.6, 27.4, 36.8, 55.6, 107.7, 114.2, 122.6, 126.8, 128.4, 130.2, 132.3,134.4, 134.7, 137.7, 156.2, 158.8, 163.7, 195.1. LCMS t=5.0 min, m/zCalcd for C₂₁H₂₂ClN₂O₃; C₂₁H₂₁ClN₂NaO₃; C₄₂H₄₃Cl₂N₄O₆; C₄₂H₄₂Cl₂N₄NaO₆385.13; 407.11; 769.26; 791.24 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found385.12; 407.10; 769.23; 791.21.

Example 04-91 Preparation of4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)benzamide(04-91)

The title compound was prepared from Example 01-36 and o-toluidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 55mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (30%yield). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.77-1.80 (m, 2H), 2.19-2.23(m, 5H), 2.26-2.28 (m, 2H), 7.17-7.24 (m, 2H), 7.28 (d, J=7.3 Hz, 1H),7.31 (d, J=7.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.87-7.89 (m, 2H), 8.13(s, 1H), 10.00 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.5, 18.3, 21.6, 27.5, 36.8,107.9, 126.5, 126.7, 127.2, 128.3, 130.3, 130.8, 134.2, 134.3, 136.5,137.8, 158.8, 164.1, 195.2. LCMS t=5.0 min, m/z Calcd for C₂₁H₂₂ClN₂O₂;C₂₁H₂₁ClN₂NaO₂; C₄₂H₄₃Cl₂N₄O₄; C₄₂H₄₃Cl₂N₄NaO₄ 369.14; 391.12; 737.27;759.25 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 369.14; 391.12; 737.27;759.25.

EXAM- PLE TITLE COMPOUND 04-# NAME R¹ R² R³ 92 Methyl 3-(4-chloro-3-((2-CO₂CH₃ H H methyl-3-oxocyclohex-1- en-1-yl)amino)benzamido)-2-methylbenzoate 93 Methyl 3-(4-chloro-3-((2- H H CO₂CH₃methyl-3-oxocyclohex-1- en-1-yl)amino)benzamido)- 4-methylbenzoate 94Methyl 4-(4-chloro-3-((2- H CO₂CH₃ H methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)- 3-methylbenzoate

Preparation of methyl3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-2-methylbenzoate(04-92)

The title compound was prepared from Example 01-36 and methyl3-amino-2-methylbenzoate according to the procedure of Example 04-13;2.0 mmol scale yielded 340 mg from precipitate (40% yield). ¹H NMR(D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.19-2.22 (m, 2H),2.27-2.29 (m, 2H), 2.34 (s, 3H), 3.85 (s, 3H), 7.35 (t, J=7.8 Hz, 1H),7.51 (d, J=7.7 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H),7.88-7.90 (m, 2H), 8.14 (s, 1H), 10.20 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.5,15.7, 21.6, 27.4, 36.8, 52.6, 107.9, 126.3, 126.8, 128.2, 128.4, 130.4,131.2, 132.0, 133.9, 134.5, 135.3, 137.7, 137.8, 158.7, 164.4, 168.1,195.2. LCMS t=5.1 min, m/z Calcd for C₂₃H₂₄ClN₂O₄; C₂₃H₂₃ClN₂NaO₄;C₄₆H₄₇Cl₂N₄O₈; C₄₆H₄₆Cl₂N₄NaO₈ 427.14; 449.12; 853.28; 875.26 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 427.16; 449.14; 853.31; 875.29.

Example 04-93 Preparation of methyl3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-4-methylbenzoate(04-93)

The title compound was prepared from Example 01-36 and methyl3-amino-4-methylbenzoate according to the procedure of Example 04-13;2.0 mmol scale yielded 310 mg from precipitate (36% yield). ¹H NMR(D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.19-2.22 (m, 2H),2.27-2.29 (m, 2H), 2.31 (s, 3H), 3.85 (s, 3H), 7.45 (d, J=7.9 Hz, 1H),7.74 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.87-7.90 (m, 2H), 7.97(s, 1H), 8.14 (s, 1H), 10.14 (s, 1H). LCMS t=5.1 min, m/z Calcd forC₂₃H₂₄ClN₂O₄; C₂₃H₂₃ClN₂NaO₄; C₄₆H₄₇Cl₂N₄O₈; C₄₆H₄₆Cl₂N₄NaO₈ 427.14;449.12; 853.28; 875.26 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 427.16;449.14; 853.32; 875.29.

Example 04-94 Preparation of methyl4-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-3-methylbenzoate(04-94)

The title compound was prepared from Example 01-36 and methyl4-amino-3-methylbenzoate according to the procedure of Example 04-13;2.0 mmol scale yielded 175 mg from precipitate (21% yield). ¹H NMR(D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.19-2.22 (m, 2H),2.29-2.32 (m, 5H), 3.86 (s, 3H), 7.58 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.1Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.85-7.90 (m, 3H), 8.11 (s, 1H), 10.10(s, 1H). ¹³C NMR (D6-DMSO) δ 9.5, 18.3, 21.6, 27.5, 36.8, 52.5, 108.0,126.5, 126.8, 127.2, 127.6, 128.3, 130.4, 131.8, 133.9, 134.0, 134.5,137.9, 141.2, 158.7, 164.3, 166.4, 195.2. LCMS t=5.1 min, m/z Calcd forC₂₃H₂₄ClN₂O₄; C₂₃H₂₃ClN₂NaO₄; C₄₆H₄₇Cl₂N₄O₈; C₄₆H₄₆Cl₂N₄NaO₈ 427.14;449.12; 853.28; 875.26 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 427.16;449.14; 853.31; 875.29.

EXAM- PLE TITLE COMPOUND 04-# NAME R¹ R² R³ 953-(4-Chloro-3-((2-methyl-3- CO₂H H H oxocyclohex-1-en-1-yl)amino)benzamido)-2- methylbenzoic acid 96 3-(4-Chloro-3-((2-methyl-3-H H CO₂H oxocyclohex-1-en-1- yl)amino)benzamido)-4- methylbenzoic acid97 4-(4-Chloro-3-((2-methyl-3- H CO₂H H oxocyclohex-1-en-1-yl)amino)benzamido)-3- methylbenzoic acid

Preparation of3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-2-methylbenzoicacid (04-95)

The title compound was prepared from Example 04-92 according to theprocedure of Example 02-01; 0.75 mmol scale yielded 0.29 g (93% yield).¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.78-1.81 (m, 2H), 2.21 (t, J=6.3 Hz,2H), 2.27-2.29 (m, 2H), 2.37 (s, 3H), 7.32 (t, J=7.8 Hz, 1H), 7.47 (d,J=8.3 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.88-7.90(m, 2H), 8.12 (s, 1H), 10.16 (s, 1H), 12.98 (s, 1H). ¹³C NMR (D6-DMSO) δ9.5, 15.7, 21.6, 27.4, 36.8, 107.9, 126.1, 126.8, 128.3, 130.4, 130.8,133.2, 133.9, 134.5, 135.2, 137.6, 137.8, 158.7, 164.4, 169.5, 195.1.LCMS t=4.7 min, m/z Calcd for C₂₂H₂₂ClN₂O₄; C₂₂H₂₁ClN₂NaO₄;C₄₄H₄₃Cl₂N₄O₈; C₄₄H₄₂Cl₂N₄NaO₈ 413.13; 435.11; 825.25; 847.23 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 413.14; 435.12; 825.28; 847.25.

Example 04-96 Preparation of3-(4-Chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-4-methylbenzoicacid (04-96)

The title compound was prepared from Example 04-93 according to theprocedure of Example 02-01; 0.7 mmol scale yielded 0.26 g (88% yield).¹H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.21 (t, J=6.4 Hz,1H), 2.26-2.30 (m, 5H), 7.41 (d, J=8.0 Hz, 1H), 7.72-7.76 (m, 2H),7.87-7.89 (m, 2H), 7.92 (s, 1H), 8.11 (s, 1H), 10.11 (s, 1H), 12.91 (s,1H). ¹³C NMR (D6-DMSO) δ 9.5, 18.6, 21.6, 27.4, 36.8, 107.9, 126.8,127.4, 127.9, 128.4, 129.3, 130.3, 131.1, 134.0, 134.5, 136.7, 137.8,139.6, 158.7, 164.3, 167.4, 195.1. LCMS t=4.7 min, m/z Calcd forC₂₂H₂₂ClN₂O₄; C₄₄H₄₃Cl₂N₄O₈ 413.13; 825.25 [M+H]⁺; [2M+H]⁺, Found413.14; 825.29.

Example 04-97 Preparation of4-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-3-methylbenzoicacid (04-97)

The title compound was prepared from Example 04-94 according to theprocedure of Example 02-01; 0.4 mmol scale yielded 0.1 g (61% yield). ¹HNMR (D6-DMSO) δ 1.66 (s, 3H), 1.78-1.81 (m, 2H), 2.21 (t, J=6.4 Hz, 1H),2.26-2.32 (m, 5H), 7.53 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.80(d, J=8.2 Hz, 1H), 7.86-7.78 (m, 3H), 8.11 (s, 1H), 10.09 (s, 1H), 12.87(s, 1H). ¹³C NMR (D6-DMSO) δ 9.5, 18.3, 21.6, 27.5, 36.8, 108.0, 126.4,126.8, 127.7, 128.3, 128.5, 130.4, 131.9, 133.7, 134.0, 134.5, 137.8,140.8, 158.7, 164.2, 167.5, 195.2. LCMS t=4.8 min, m/z Calcd forC₂₂H₂₂ClN₂O₄; C₂₂H₂₁ClN₂NaO₄; C₄₄H₄₃Cl₂N₄O₈; C₄₄H₄₂Cl₂N₄NaO₈ 413.13;825.25 [M+H]⁺; [2M+H]⁺, Found 413.14; 825.28.

Example 04-98 Preparation ofN-(4-methoxyphenyl)-2-(3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-acetamide(04-98)

The title compound was prepared from Example 01-37 and p-anisidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 10mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (6%yield). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.75-1.78 (m, 2H), 2.18-2.21(m, 2H), 2.42-2.45 (m, 2H), 3.59 (s, 2H), 3.71 (s, 3H), 6.87 (d, J=8.7Hz, 2H), 6.99 (d, J=7.5 Hz, 1H), 7.08 (s, 2H), 7.28 (t, J=7.8 Hz, 1H),7.49 (d, J=8.7 Hz, 2H), 8.20 (s, 1H), 10.01 (s, 1H). ¹³C NMR (D6-DMSO) δ9.7, 22.1, 27.8, 36.9, 43.5, 55.6, 107.6, 114.3, 121.1, 122.9, 125.4,129.1, 129.1, 132.8, 137.3, 140.3, 155.6, 158.5, 168.8, 194.8. LCMSt=4.9 min, m/z Calcd for C₂₂H₂₅N₂O₃; C₂₂H₂₄N₂NaO₃; C₄₄H₄₉N₄O₆;C₄₄H₄₈N₄NaO₆ 365.19; 387.17; 729.37; 751.35 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 365.17; 387.14; 729.31; 751.29.

EXAM- PLE TITLE COMPOUND 04-# NAME R¹ R² 99N-(4-Methoxyphenyl)-2-(4-((2-methyl-3- H OCH₃ oxocyclohex-1-en-1-yl)amino)phenyl)acetamide 100 2-(4-((2-Methyl-3-oxocyclohex-1-en-1- CH₃H yl)amino)phenyl)-N-(o-tolyl)acetamide

Example 04-99 Preparation ofN-(4-methoxyphenyl)-2-(4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-acetamide(04-99)

The title compound was prepared from Example 01-38 and p-anisidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 31mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (17%yield). ¹H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.75-1.77 (m, 2H), 2.17-2.20(m, 2H), 2.41-2.43 (m, 2H), 3.57 (s, 2H), 3.71 (s, 3H), 6.87 (d, J=8.6Hz, 2H), 7.08 (d, J=7.8 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 7.50 (d, J=8.6Hz, 2H), 8.14 (s, 1H), 10.00 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.5, 22.1,27.7, 36.9, 43.0, 55.6, 107.0, 115.3, 121.1, 125.0, 129.8, 132.5, 132.8,138.7, 156.0, 158.8, 169.0, 194.6. LCMS t=4.8 min, m/z Calcd forC₂₂H₂₅N₂O₃; C₂₂H₂₄N₂NaO₃; C₄₄H₄₉N₄O₆; C₄₄H₄₈N₄NaO₆ 365.19; 387.17;729.37; 751.35 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 365.16; 387.14;729.30; 751.28.

Example 04-100 Preparation of2-(4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-N-(o-tolyl)acetamide(04-100)

The title compound was prepared from Example 01-37 and o-toluidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 40mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (23%yield). ¹H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.75-1.78 (m, 2H), 2.16 (s,3H), 2.18-2.21 (m, 2H), 2.41-2.44 (m, 2H), 3.65 (s, 3H), 7.05-7.21 (m,5H), 7.27-7.39 (m, 3H), 8.18 (s, 1H), 9.49 (s, 1H). ¹³C NMR (D6-DMSO) δ9.5, 18.2, 22.2, 27.7, 36.9, 42.6, 106.9, 112.6, 119.5, 125.0, 125.5,125.7, 126.4, 129.8, 130.7, 132.2, 132.7, 136.7, 138.7, 158.9, 169.5,194.6. LCMS t=4.7 min, m/z Calcd for C₂₂H₂₅N₂O₂; C₂₂H₂₄N₂NaO₂;C₄₄H₄₉N₄O₄; C₄₄H₄₈N₄NaO₄ 349.19; 371.17; 697.37; 719.36 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 349.18; 371.14; 697.31; 719.29.

EXAM- PLE TITLE COMPOUND 04-# NAME R¹ R² 101N-(4-Methoxyphenyl)-3-((2-methyl-3- H OCH₃oxocyclohex-1-en-1-yl)amino)-4- (trifluoromethyl)benzamide 1023-((2-Methyl-3-oxocyclohex-1-en-1- CH₃ H yl)amino)-N-(o-tolyl)-4-(trifluoromethyl)benzamide

Example 04-101 Preparation ofN-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-4-(trifluoromethyl)benzamide(04-101)

The title compound was prepared from Example 01-39 and p-anisidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 10mg after chromatography (ESS=H:E (1:1)) and EtOAc trituration (5%yield). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.75-1.77 (m, 2H), 2.19-2.21(m, 4H), 3.76 (s, 3H), 6.95 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H),7.95 (s, 2H), 8.00 (s, 1H), 8.05-8.07 (m, 1H), 10.32 (s, 1H). ¹³C NMR(D6-DMSO) δ 9.2, 21.6, 27.6, 36.7, 55.5, 107.2, 114.3, 122.7, 126.6,127.5, 129.2 (J_(CF)=28.8 Hz), 130.1, 132.0, 138.8, 139.7, 156.4, 159.2,163.4, 195.0. LCMS t=5.1 min, m/z Calcd for C₂₂H₂₂F₃N₂O₃;C₂₂H₂₁F₃N₂NaO₃; C₄₄H₄₃F₆N₄O₆; C₄₄H₄₂F₆N₄NaO₆ 419.16; 441.14; 837.31;859.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 419.14; 441.09; 837.22;859.20.

Example 04-102 Preparation of3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)-4-(trifluoromethyl)benzamide(04-102)

The title compound was prepared from Example 01-39 and o-toluidineaccording to the procedure of Example 04-13; 0.50 mmol scale 10 mg afterchromatography (ESS=H:E (1:1)) and EtOAc trituration (5% yield). ¹H NMR(D6-DMSO) δ 1.65 (s, 3H), 1.75-1.78 (m, 2H), 2.18-2.24 (m, 7H),7.19-7.26 (m, 2H), 7.30 (d, J=7.3 Hz, 1H), 7.34 (d, J=7.4 Hz, 1H),7.93-7.99 (3H), 8.07 (d, J=7.9 Hz, 1H), 10.15 (s, 1H). ¹³C NMR (D6-DMSO)δ 9.3, 18.3, 21.6, 27.6, 36.7, 107.4, 126.6, 127.0, 127.2, 127.6, 129.2(J_(CF)=29.9 Hz), 130.0, 130.9, 134.4, 136.3, 139.0, 139.3, 159.1,163.8, 195.0. LCMS t=5.1 min, m/z Calcd for C₂₂H₂₂F₃N₂O₂;C₂₂H₂₁F₃N₂NaO₂; C₄₄H₄₃F₆N₄O₄; C₄₄H₄₂F₆N₄NaO₄ 403.16; 425.15; 805.32;827.30 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 403.15; 425.10; 805.24;827.22.

Example 04-103 Preparation ofN-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-3-(trifluoromethyl)benzamide(04-103)

The title compound was prepared from Example 01-40 and p-anisidineaccording to the procedure of Example 04-13; 0.50 mmol scale yielded 60mg after chromatography (ESS=H:E (1:1)) and EtOAc trituration (31%yield). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 1.77-1.80 (m, 2H), 2.21-2.24(m, 2H), 2.29-1.31 (m, 2H), 3.75 (s, 3H), 6.95 (d, J=8.6 Hz, 2H), 7.46(d, J=8.3 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.91 (s, 1H), 8.23 (d, J=8.3Hz, 1H), 8.30 (s, 1H), 10.33 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.8, 21.5,28.1, 36.9, 55.6, 109.6, 114.2, 122.6, 123.9 (J_(CF)=273.6 Hz), 124.8(J_(CF)=87.6, 29.2 Hz), 126.5, 129.7, 132.3, 132.4, 132.8, 141.6, 156.2,158.2, 163.6, 195.7. LCMS t=5.1 min, m/z Calcd for C₂₂H₂₂F₃N₂O₃;C₂₂H₂₁F₃N₂NaO₃; C₄₄H₄₃F₆N₄O₆; C₄₄H₄₂F₆N₄NaO₆ 419.16; 441.14; 837.31;859.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 419.14; 441.09; 837.22;859.20

Example 04-104 Preparation of3-iodo-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(04-104)

The title compound was prepared from Example 02-08 and p-anisidineaccording to the procedure of Example 04-13; 0.15 mmol scale yielded 110mg of pale yellow microcrystals after chromatography (ESS H:E=1:19,mp=222-224° C., 52% yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.22(m, 2H), 2.41-2.46 (m, 1H), 3.75 (s, 3H), 6.94 (d, J=8.9 Hz, 2H), 7.46(d, J=8.2 Hz, 1H), 7.66 (d, J=8.9 Hz, 2H), 7.98 (dd, J=8.1, 1.2 Hz, 1H),8.47 (d, J=1.3 Hz, 1H), 8.90 (s, 1H), 10.21 (s, 1H). ¹³C NMR (D6-DMSO) δ7.5, 25.7, 32.7, 55.2, 98.6, 109.6, 113.8, 122.1, 127.2, 128.4, 132.0,133.9, 138.0, 144.0, 155.7, 162.9, 169.1, 202.3. LCMS t=4.9 min, Calcdfor C₂₀H₂₀IN₂O₃; C₂₀H₁₉IN₂NaO₃; C₄₀H₃₉I₂N₄O₆; C₄₀H₃₈I₂N₄NaO₆ 463.05;485.03; 925.10; 947.09 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 463.08;485.00; 925.11; 947.09.

EXAM- PLE TITLE COMPOUND 04-# NAME R¹ R² 105N-(4-Methoxyphenyl)-3-((2-methyl-3- H OCH₃oxocyclohex-1-en-1-yl)amino)-1-naphthamide 1063-((2-Methyl-3-oxocyclohex-1-en-1-yl)amino)- CH₃ HN-(o-tolyl)-1-naphthamide

Example 04-105 Preparation ofN-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-1-naphthamide(04-105)

The title compound was prepared from Example 01-52 and p-anisidineaccording to the procedure of Example 04-13; 0.5 mmol scale yielded 1 mgof off-white microcrystals after chromatography (ESS E:H=1:1, 1% yield).¹H NMR (D6-DMSO) δ 1.74 (s, 3H), 1.83-1.86 (m, 2H), 2.25-2.28 (m, 2H),2.63-2.65 (m, 2H), 3.76 (s, 3H), 6.95 (d, J=8.8 Hz, 2H), 7.47-7.50 (m,1H), 7.53-7.58 (m, 2H), 7.67 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.92 (d,J=8.1 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 10.43 (s, 1H). ¹³CNMR (D6-DMSO) δ 9.4, 21.8, 27.5, 36.5, 55.2, 108.5, 113.9, 121.0, 121.4,122.9, 125.1, 125.7, 126.5, 126.9, 127.7, 132.3, 133.8, 135.7, 136.8,155.6, 157.8, 166.2, 194.7. LCMS t=4.7 min, Calcd for C₂₅H₂₅N₂O₃;C₂₅H₂₄N₂NaO₃; C₅₀H₄₉N₄O₆; C₅₀H₄₈N₄NaO₆ 401.187; 423.169; 801.365;823.347 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 401.184; 423.138;801.345; 823.331.

Example 04-106 Preparation of3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)-1-naphthamide(04-106)

The title compound was prepared from Example 01-52 and o-toluidineaccording to the procedure of Example 04-13; 0.5 mmol scale yielded 12mg of pale yellow microcrystals after chromatography (ESS=1:1,mp=249-250° C. decomp, 7% yield). ¹H NMR (D6-DMSO) δ 1.75 (s, 3H),1.83-1.86 (m, 2H), 2.26-2.29 (m, 2H), 2.34 (s, 3H), 2.64-2.66 (m, 2H),7.18-7.21 (m, 1H), 7.24-7.31 (m, 3H), 7.48-7.57 (m, 3H), 7.66 (d, J=15.7Hz, 2H), 7.93 (d, J=8.0 Hz, 1H), 8.18 (d, J=8.2 Hz, 1H), 8.48 (s, 1H),10.07 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.4, 18.1, 21.9, 36.6, 108.6, 121.2,123.0, 125.1, 125.7, 126.1, 126.3, 126.7, 126.9, 127.7, 130.4, 133.3,133.8, 135.5, 136.2, 136.8, 157.7, 166.9, 194.8. LCMS t=5.0 min, Calcdfor C₂₅H₂₅N₂O₂; C₂₅H₂₄N₂NaO₂; C₅₀H₄₉N₄O₄; C₅₀H₄₈N₄NaO₄ 385.19; 407.17;769.37; 791.36 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 385.18; 407.16;769.35; 791.34.

Examples 05-01 to 05-86

Example 05-01 Preparation of3-((3-chlorophenyl)amino)-2-methylcyclopent-2-enone (05-01)

2-Methyl-1,3-cyclopentandione (112 mg, 1.0 mmol, 1.0 eq) and3-chloroaniline (106 □L, 1.0 eq) were mixed and treated with AcOH (200□L, 3.5 eq). Microwave irradiation was applied to a sealed microwavevial for 10 min in a single mode Biotage®-Initiator cavity, producingcontinuous irradiation to hold temp at 2.45 GHz. The crude products wererecrystallized, or were added directly to a KP-Sil™ column (10 g) in asmall amount of CH₂Cl₂ with products separating from impurities usingstepwise gradients on the Biotage®-Isolera Four instrument, monitoringUV Trace at 254/365 nm. The reaction on a 1.0 mmol scale yielded 90 mgof the title compound after recrystallization from EtOAc (41% yield). ¹HNMR (D6-DMSO) δ 1.58 (s, 3H), 2.21-2.23 (m, 2H), 2.70-2.72 (m, 2H), 7.15(d, J=7.8 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.35 (s, 1H), 7.36 (t, J=8.0Hz, 1H), 9.02 (s, 1H). LCMS t=5.7 min, m/z Calcd for C₁₂H₁₃ClNO;C₁₂H₁₂ClNNaO; C₂₄H₂₅Cl₂N₂O₂; C₂₄H₂₄Cl₂N₂NaO₂ 222.07; 244.05; 443.13;465.11 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 222.07; 244.05; 443.13;465.11.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ R² R³ R⁴ 022-Benzyl-3-((4-methoxy- H H H OCH₃ phenyl)amino)cyclopent-2-enone 032-(4-((2-Benzyl-3-oxocyclopent-1- H H H CH₂CNen-1-yl)amino)phenyl)acetonitrile 04 Methyl 4-((2-benzyl-3-oxocyclopent-H Cl H CO₂CH₃ 1-en-1-yl)amino)-3-chlorobenzoate

Example 05-02 Preparation of2-benzyl-3-((4-methoxyphenyl)amino)cyclopent-2-enone (05-02)

The title compound was prepared from Intermediate 01 and p-anisidineaccording to the procedure of Example 05-01; 0.53 mmol scale yielded 30mg after chromatography (ESS=H:E (1:3)) and recrystallization from EtOAc(19% yield). ¹H NMR (D6-DMSO) δ 2.18-2.20 (m, 2H), 2.54-2.56 (m, 2H),3.48 (s, 2H), 3.75 (s, 3H), 6.91 (d, J=8.8 Hz, 2H), 7.10-7.13 (m, 1H),7.15 (d, J=8.7 Hz, 2H), 7.21-7.23 (m, 4H), 9.03 (s, 1H). ¹³C NMR(D6-DMSO) δ 25.4, 26.8, 32.5, 55.3, 112.0, 114.1, 125.4, 125.9, 128.0,128.1, 132.1, 140.9, 156.7, 170.9, 201.1. LCMS t=5.1 min, m/z Calcd forC₁₉H₂₀NO₂; C₁₉H₁₉NNaO₂; C₃₈H₃₉N₂O₄; C₃₈H₃₈N₂NaO₄ 294.15; 316.13; 587.29;609.28 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 294.18; 316.14; 587.24;609.34.

Example 05-03 Preparation of2-(4-((2-benzyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)acetonitrile(05-03)

The title compound was prepared from Intermediate 01 and 4-aminobenzylcyanide according to the procedure of Example 05-01; 0.53 mmol scaleyielded 10 mg after chromatography (ESS=H:E (1:3)) and recrystallizationfrom EtOAc (6% yield). ¹H NMR (D6-DMSO) δ 2.23-2.25 (m, 2H), 2.70-2.72(m, 2H), 3.53 (s, 2H), 4.01 (s, 2H), 7.10-7.3 (m, 1H), 7.19-7.24 (4H),7.26 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 9.19 (s, 1H). ¹³C NMR(D6-DMSO) δ 21.8, 25.6, 26.8, 32.8, 113.5, 119.3, 123.6, 125.4, 127.1,128.0, 128.1, 128.8, 139.0, 140.6, 169.8, 201.5. LCMS t=4.9 min, m/zCalcd for C₂₀H₁₉N₂O; C₂₀H₁₈N₂NaO; C₄₀H₃₇N₄O₂; C₄₀H₃₆N₄NaO₂ 303.15;325.13; 605.29; 627.27 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 303.17;332.15; 605.24 627.25.

Example 05-04 Preparation of methyl4-((2-benzyl-3-oxocyclopent-1-en-1-yl)amino)-3-chlorobenzoate (05-04)

The title compound was prepared from Intermediate 01 and methyl4-amino-3-chlorobenzoate according to the procedure of Example 05-01;1.07 mmol scale and 30 min irradiation, yielded 20 mg afterchromatography (ESS=H:E (1:3)) and recrystallization from EtOAc (5%yield). ¹H NMR (D6-DMSO) δ 2.28-2.30 (m, 2H), 2.59-2.61 (m, 2H), 3.46(s, 2H), 3.86 (s, 3H), 7.05-7.12 (m, 3H), 7.14-7.20 (m, 2H), 7.50 (d,J=8.1 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 9.01 (s, 1H). ¹³CNMR (D6-DMSO) δ 25.8, 27.3, 32.7, 52.5, 114.9, 125.6, 126.9, 127.9,128.0, 128.5, 130.3, 139.9, 140.6, 164.7, 168.7, 202.5. LCMS t=5.3 min,m/z Calcd for C₂₀H₁₉ClNO₃; C₂₀H₁₈ClNNaO₃; C₄₀H₃₆Cl₂N₂NaO₆ 356.11;378.09; 733.18 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 356.11; 378.07; 733.15.

Example 05-05 Preparation of2-(4-hydroxybenzyl)-3-((4-methoxyphenyl)amino)cyclopent-2-enone (05-05)

The title compound was prepared from Intermediate 02 and p-anisidineaccording to the procedure of Example 05-01; 0.5 mmol scale yielded 20mg after chromatography (ESS=EtOAc) and recrystallization from EtOAc(13% yield). ¹H NMR (D6-DMSO) δ 2.17-2.19 (m, 2H), 2.50-2.53 (m, 2H),3.37 (s, 2H), 3.75 (3H), 6.61 (d, J=7.8 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H),7.00 (d, J=7.8 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 8.96 (s, 1H), 9.05 (s,1H). ¹³C NMR (D6-DMSO) δ 25.3, 25.9, 32.5, 55.3, 112.8, 114.1, 114.7,125.8, 129.0, 130.9 132.2, 155.1, 156.7, 170.6, 201.1. LCMS t=4.7 min,m/z Calcd for C₁₉H₂₀NO₃; C₁₉H₁₉NNaO₃; C₃₈H₃₉N₂O₆; C₃₈H₃₈N₂NaO₆ 310.14;332.13; 619.28; 641.26 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 310.17;332.13; 619.23; 641.25.

EXAM- PLE TITLE COMPOUND 05-# NAME X Y 06 2-Benzyl-3-(quinolin-3- CH Nylamino)cyclopent-2-enone 07 2-Benzyl-3-(quinolin-2- N CHylamino)cyclopent-2-enone

Example 05-06 Preparation of2-benzyl-3-(quinolin-3-ylamino)cyclopent-2-enone (05-06)

The title compound was prepared from Intermediate 01 and3-aminoquinoline according to the procedure of Example 05-01; 0.53 mmolscale yielded 15 mg after chromatography (ESS=H:E (1:3)) andrecrystallization from EtOAc (9% yield). ¹H NMR (D6-DMSO) δ 2.30-2.32(m, 2H), 2.86-2.88 (m, 2H), 3.59 (s, 2H), 7.12-7.15 (m, 1H), 7.22-7.24(m, 4H), 7.60 (t, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.93 (d, J=8.1Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 8.84 (d, J=2.1Hz, 1H), 9.48 (s, 1H). ¹³C NMR (D6-DMSO) δ 25.6, 26.9, 32.9, 114.7,125.6, 125.7, 127.2, 127.6, 127.8, 128.1, 128.3, 128.6, 133.4, 140.3,144.5, 147.5, 169.6, 201.9. LCMS t=4.9 min, m/z Calcd for C₂₁H₁₉N₂O;C₂₁H₁₈N₂NaO; C₄₂H₃₇N₄O₂; C₄₂H₃₆N₄NaO₂ 315.15; 337.13; 629.29; 651.27[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 315.17; 337.14; 629.24;651.29.

Example 05-07 Preparation of2-benzyl-3-(quinolin-2-ylamino)cyclopent-2-enone (05-07)

The title compound was prepared from Intermediate 01 and2-aminoquinoline according to the procedure of Example 05-01; 0.53 mmolscale yielded 5 mg after chromatography (ESS=H:E (1:3)) andrecrystallization from EtOAc (3% yield). ¹H NMR (D6-DMSO) δ 2.35-2.37(m, 2H), 3.52-3.54 (m, 2H), 3.68 (s, 2H), 7.11-7.14 (m, 1H), 7.22-7.25(m, 4H), 7.39 (d, J=8.8 Hz, 1H), 7.42 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.4Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 8.23 (d, J=8.8Hz, 1H), 9.74 (s, 1H). ¹³C NMR (D6-DMSO) δ 26.7, 28.5, 33.2, 114.7,117.8, 124.4, 125.6, 127.1, 127.7, 128.0, 128.1, 129.9, 138.0, 140.2,146.3, 152.5, 168.0, 203.4. LCMS t=5.4 min, m/z Calcd for C₂₁H₁₉N₂O;C₂₁H₁₈N₂NaO; C₄₂H₃₇N₄O₂; C₄₂H₃₆N₄NaO₂ 315.15; 337.13; 629.29; 651.27[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 315.17; 337.13; 629.25;651.32.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ R² R³ 083-((3-Chlorophenyl)amino)-2- H Cl H methylcyclohex-2-enone 092-Methyl-3-(o-tolylamino)cyclohex- CH₃ H H 2-enone 102-Methyl-3-(m-tolylamino)cyclohex- H CH₃ H 2-enone 112-Methyl-3-(p-tolylamino)cyclohex- H H CH₃ 2-enone 12 Methyl3-chloro-4-((2-methyl-3- Cl H CO₂CH₃ oxocyclohex-1-en-1-yl)amino)ben-zoate

Example 05-08 Preparation of3-((3-chlorophenyl)amino)-2-methylcyclohex-2-enone (05-08)

The title compound was prepared from 2-methyl-1,3-cyclohexandione and3-chloroaniline according to the procedure of Example 05-01; 1.59 mmolscale yielded 300 mg after chromatography (ESS=CH₂Cl₂:EtOAc (9:1), 80%yield). ¹H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.78-1.81 (m, 2H), 2.21-2.24(m, 2H), 2.47-2.50 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 7.12-7.15 (m, 2H),7.33 (t, J=7.9 Hz, 1H), 8.26 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.5, 21.7,27.5, 36.5, 108.8, 121.9, 122.9, 123.2, 130.3, 133.0, 141.7, 157.2,195.0. LCMS t=5.1 min, m/z Calcd for C₁₃H₁₅ClNO; C₁₃H₁₄ClNNaO;C₂₆H₂₉Cl₂N₂O₂; C₂₆H₂₈Cl₂N₂NaO₂ 236.08; 258.07; 471.16; 493.14 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 236.10; 258.07; 471.14; 493.16.

Example 05-09 Preparation of 2-methyl-3-(o-tolylamino)cyclohex-2-enone(05-09)

The title compound was prepared from 2-methyl-1,3-cyclohexandione ando-toluidine according to the procedure of Example 05-01; 1.59 mmol scaleyielded 130 mg after chromatography (ESS=CH₂Cl₂:EtOAc (9:1), 38% yield).¹H NMR (D6-DMSO) δ 1.67-1.73 (m, 5H), 2.13-2.21 (m, 7H), 7.11 (d, J=6.8Hz, 1H), 7.18-7.22 (m, 2H), 7.28 (d, J=6.4 Hz, 1H), 7.84 (s, 1H). ¹³CNMR (D6-DMSO) δ 8.7, 17.7, 21.3, 26.8, 36.3, 105.0, 126.3, 126.4, 128.1,130.5, 135.2, 138.4, 159.7, 193.8. LCMS t=4.9 min, m/z Calcd forC₁₄H₁₈NO; C₁₄H₁₇NNaO; C₂₈H₃₅N₂O₂; C₂₈H₃₄N₂NaO₂ 216.14; 238.12; 431.27;453.25 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 216.17; 238.12; 431.27;453.46.

Example 05-10 Preparation of 2-methyl-3-(m-tolylamino)cyclohex-2-enone(05-10)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andm-toluiline according to the procedure of Example 05-01; 1.59 mmol scaleyielded 190 mg after chromatography (ESS=CH₂Cl₂:EtOAc (9:1), 56% yield).¹H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.74-1.79 (m, 2H), 2.17-2.20 (m, 2H),2.29 (s, 3H), 2.41-2.44 (m, 2H), 6.91 (d, J=8.3 Hz, 1H), 6.94-6.96 (m,2H), 7.21 (t, J=7.7 Hz, 1H), 8.12 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.1,20.9, 21.7, 27.3, 36.5, 106.7, 121.6, 124.9, 125.1, 128.6, 138.1, 139.7,158.3, 194.3. LCMS t=5.0 min, m/z Calcd for C₁₄H₁₈NO; C₁₄H₁₇NNaO;C₂₈H₃₅N₂O₂; C₂₈H₃₄N₂NaO₂ 216.14; 238.12; 431.27; 453.25 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 216.22; 238.12; 431.27; 453.25.

Example 05-11 Preparation of 2-methyl-3-(p-tolylamino)cyclohex-2-enone(05-11)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andp-toluiline according to the procedure of Example 05-01; 1.59 mmol scaleyielded 160 mg after chromatography (ESS=CH₂Cl₂:EtOAc (9:1), 47% yield).¹H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.74-1.77 (m, 2H), 2.16-2.19 (m, 2H),2.28 (s, 3H), 2.36-2.29 (m, 2H), 7.02 (d, J=8.0 Hz, 2H), 7.15 (d, J=7.8Hz, 2H), 8.09 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.0, 20.5, 21.7, 27.1, 36.4,106.0, 124.9, 129.2, 133.6, 137.2, 158.7, 194.0. LCMS t=5.0 min, m/zCalcd for C₁₄H₁₈NO; C₁₄H₁₇NNaO; C₂₈H₃₅N₂O₂; C₂₈H₃₄N₂NaO₂ 216.14; 238.12;431.27; 453.25 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 216.17; 238.12;431.27; 453.26.

Example 05-12 Preparation of methyl3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoate (05-10)

The title compound was prepared from 2-methyl-1,3-cyclohexandione andmethyl 4-amino-3-chlorobenzoate according to the procedure of Example05-01; 1.59 mmol scale, irradiation for 30 min, yielded 260 mg afterchromatography (ESS=CH₂Cl₂:EtOAc (9:1), 56% yield). ¹H NMR (D6-DMSO) δ1.52 (s, 3H), 1.81-1.83 (m, 2H), 2.24-2.27 (m 2H), 2.42-2.43 (m, 2H),3.85 (s, 3H), 7.18 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.98 (s,1H), 8.06 (s, 1H). LCMS t=5.1 min, m/z Calcd for C₁₅H₁₇ClNO₃;C₁₅H₁₆ClNNaO₃; C₃₀H₃₃Cl₂N₂O₆; C₃₀H₃₂Cl₂N₂NaO₆ 294.09; 316.07; 587.17;609.15 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 294.12; 316.09; 587.13;609.15.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ R² 133-Chloro-N-(4-methoxyphenyl)-4-((2- H OCH₃ methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide 14 3-Chloro-N-(2-methoxyphenyl)-4-((2- OCH₃ Hmethyl-3-oxocyclohex-1-en-1- yl)amino)benzamide 153-Chloro-4-((2-methyl-3- CH₃ H oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)benzamide

Example 05-13 Preparation of3-chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide(05-13)

Example 05-12 (239 mg, 0.82 mmol) was hydrolyzed to3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid to theprocedure of Example 02-01. The title compound was prepared from3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid andp-anisidine according to the procedure of Example 04-13; 0.21 mmol scaleyielded 10 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration(12% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.80-1.82 (m, 2H),2.22-2.25 (m, 2H), 2.36-2.38 (m, 2H), 3.75 (s, 3H), 6.94 (d, J=8.8 Hz,2H), 7.31 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.7 Hz, 2H), 7.91 (d, J=8.2 Hz,1H), 8.06 (s, 1H), 8.11 (s, 1H), 10.18 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.6,12.1, 27.6, 36.5, 55.2, 109.7, 113.8, 122.0, 126.6, 127.1, 128.4, 128.8,132.0, 132.1, 140.1, 155.7, 157.3, 163.1, 195.3. LCMS t=5.0 min, m/zCalcd for C₂₁H₂₂ClN₂O₃; C₂₁H₂₁ClN₂NaO₃; C₄₂H₄₃Cl₂N₄O₆; C₄₂H₄₂Cl₂N₄NaO₆385.13; 407.11; 769.26; 791.24 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found385.12; 407.09; 769.22; 791.22.

Example 05-14 Preparation of3-chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide(05-14)

The title compound was prepared from3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid ando-anisidine according to the procedure of Example 05-13; 0.21 mmol scaleyielded 5 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration(6% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.80-1.87 (m, 2H),2.23-2.25 (m, 2H), 2.37-2.39 (m, 2H), 3.83 (s, 3H), 6.96-7.01 (m, 1H),7.10-7.15 (m, 1H), 7.21-7.26 (m, 1H), 7.30-7.35 (m, 1H), 7.67 (d, J=6.3Hz, 1H), 7.92 (d, J=6.9 Hz, 1H), 8.07 (s, 1H), 8.11 (s, 1H), 9.60 (s,1H). ¹³C NMR (D6-DMSO) δ 9.7, 21.1, 27.6, 36.5, 55.7, 109.9, 111.5,120.2, 125.2, 126.2, 126.5, 126.6, 127.0, 128.4, 129.0, 131.6, 140.3,152.0, 157.3, 163.3, 195.4. LCMS t=5.3 min, m/z Calcd for C₂₁H₂₂ClN₂O₃;C₂₁H₂₁ClN₂NaO₃; C₄₂H₄₃Cl₂N₄O₆; C₄₂H₄₂Cl₂N₄NaO₆ 385.13; 407.11; 769.26;791.24 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 385.13; 407.09; 769.20;791.39.

Example 05-15 Preparation of3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)benzamide(05-15)

The title compound was prepared from3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid ando-toluidine according to the procedure of Example 05-13; 0.21 mmol scaleyielded 2 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration(3% yield). ¹H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.79-1.88 (m, 2H),2.20-2.32 (m, 5H), 2.34-2.45 (m, 2H), 7.15-7.39 (m, 5H), 7.93 (s, 1H),8.07 (s, 1H), 8.12 (s, 1H), 9.96 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.7, 17.9,21.1, 27.6, 36.5, 109.8, 126.0, 126.2, 126.7, 127.1, 128.5, 129.0,130.4, 131.7, 133.8, 136.2, 140.3, 157.3, 163.5, 195.4. LCMS t=5.2 min,m/z Calcd for C₂₁H₂₂ClN₂O₂; C₂₁H₂₁ClN₂NaO₂; C₄₂H₄₂Cl₂N₄NaO₄ 369.14;391.12; 759.25 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 369.14; 391.10; 759.24.

Example 05-16 Preparation of4-((2-benzyl-3-oxocyclopent-1-en-1-yl)amino)-3-chloro-N-(o-tolyl)benzamide(05-16)

The title compound was prepared from Intermediate 01 and free baseIntermediate 03 according to the procedure of Example 05-13; 0.25 mmolscale yielded 5 mg after chromatography (ESS=H:E (1:3)) andrecrystallization from MeOH (5% yield). ¹H NMR (D6-DMSO) δ 2.24 (s, 3H),2.27-2.28 (m, 2H), 2.56-2.58 (m, 2H), 3.50 (s, 2H), 7.12-7.24 (m, 7H),7.28 (d, J=7.0 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H),7.94 (d, J=7.9 Hz, 1H), 8.10 (s, 1H), 9.06 (s, 1H), 10.00 (s, 1H). LCMSt=5.6 min, m/z Calcd for C₂₆H₂₄ClN₂O₂; C₂₆H₂₃ClN₂NaO₂; C₅₂H₄₇Cl₂N₄O₄;C₅₂H₄₆Cl₂N₄NaO₄ 431.15; 453.13; 861.30; 883.28 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 431.15; 453.13; 861.30; 883.28.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ 173-Fluoro-N-(4-methoxyphenyl)-4-((2-methyl-3- Foxocyclopent-1-en-1-yl)amino)benzamide 183-Bromo-N-(4-methoxyphenyl)-4-((2-methyl-3- Broxocyclopent-1-en-1-yl)amino)benzamide

Example 05-17 Preparation of3-fluoro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(05-17)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andfree base Intermediate 04 according to the procedure of Example 05-13;0.25 mmol scale yielded 50 mg after recrystallization from MeOH (56%yield). ¹H NMR (D6-DMSO) δ 1.54 (s, 3H), 2.22-2.25 (m, 2H), 2.50-2.52(m, 2H), 3.75 (s, 3H), 6.92-6.95 (m, 2H), 7.44-7.48 (m, 1H), 7.65-7.67(m, 2H), 7.80-7.82 (m, 1H), 7.88 (dd, J=11.3, 1.7 Hz, 1H), 9.03 (s, 1H),10.15 (s, 1H). LCMS t=4.8 min, m/z Calcd for C₂₀H₂₀FN₂O₃; C₂₀H₁₉FN₂NaO₃;C₄₀H₃₉F₂N₄O₆; C₄₀H₃₈F₂N₄NaO₆ 355.15; 377.13; 709.28; 731.27 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.17; 377.10; 709.24; 731.22.

Example 05-18 Preparation of3-bromo-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(05-18)

The title compound was prepared from 2-methyl-1,3-cyclopentandione andfree base Intermediate 05 according to the procedure of Example 05-13;0.25 mmol scale yielded 10 mg after recrystallization from MeOH (10%yield). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.21-2.24 (m, 2H), 2.47-2.49(m, 2H), 3.75 (s, 3H), 6.93-6.95 (m, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.66(d, J=8.9 Hz, 2H), 7.97 (dd, J=8.2, 1.6 Hz, 1H), 8.27 (d, J=1.7 Hz, 1H),8.93 (s, 1H), 10.22 (s, 1H). LCMS t=4.9 min, m/z Calcd for C₂₀H₂₀BrN₂O₃;C₂₀H₁₉BrN₂NaO₃; C₄₀H₃₉Br₂N₄O₆; C₄₀H₃₈Br₂N₄NaO₆ 415.07, 417.06; 437.05,439.05; 831.12; 853.10 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 415.05,417.05; 437.01, 439.01; 831.05; 853.03.

Example 05-19 Preparation of tert-butyl(2-(4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)ethyl)-carbamate(05-19)

tert-Butyl-N-(2-aminoethyl)carbamate (1.4 mL, 1.03 eq) was added toExample 02-01 (2.0 g, 8.65 mmol) stirring in CH₂C₁₂:DMF (90 mL, 1:1) at0° C. 3-(Ethyliminomethylene-amino)-N,N-dimethyl-propan-1-aminehydrochloride (EDCCl, 2.0 g, 1.2 eq) was added and stirred for 2 h at 0°C. After warming to rt overnight, the solvent was removed on therotovap. Work-up was performed with DI H₂O (500 mL) and EtOAc (8×125mL). The organic layer was dried over anhyd sodium sulfate andconcentrated on the rotovap. Crude material was added directly to aKP-Sil™ column (100 g) with products separating from impurities usingstepwise gradients on the Biotage®-Isolera Four instrument, monitoringUV Trace at 254/365 nm. The reaction on a 8.65 mmol scale yielded 1.5 gof the title compound after chromatography (ESS=EtOAc, 46% yield). ¹HNMR (D6-DMSO) δ 1.37 (s, 9H), 1.59 (s, 3H), 2.23-2.25 (m, 2H), 2.75-2.77(m, 2H), 3.08-3.10 (m, 2H), 3.26-3.28 (m, 2H), 6.92 (s, 1H), 7.29 (d,J=8.0 Hz, 2H), 7.81 (d, J=7.8 Hz, 2H), 8.38 (s, 1H), 9.11 (s, 1H). LCMSt=Direct Injection, m/z Calcd for C₂₀H₂₈N₃O₄; C₂₀H₂₇N₃NaO₄; C₄₀H₅₄N₆NaO₈374.21; 396.19; 769.39 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 374.21; 396.19;769.39.

Example 05-20 Preparation of2-(4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)ethanaminium2,2,2-trifluoroacetate (05-20)

Example 05-19 (750 mg, 2.0 mmol) was stirred in a minimum amount ofCH₂Cl₂:TFA (1:1) for 30 min at rt. Solvents were removed on the rotovapand the title compound was recrystallized from EtOAc. ¹H NMR (MeOD) δ1.68 (s, 3H), 2.41-2.43 (m, 2H), 2.84-2.86 (m, 2H), 3.15-3.18 (m, 2H),3.65-3.67 (m, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H). LCMSt=3.0 min, m/z Calcd for C₁₅H₂₀N₃O₂; C₁₅H₁₉N₃NaO₂; C₃₀H₃₉N₆O₄;C₃₀H₃₈N₆NaO₄ 274.16; 296.14; 547.30; 569.29 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 274.20; 296.17; 547.27; 569.26.

Example 05-21 Preparation ofN-(2-acetamidoethyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(05-21)

Anhydride N-Acylation; Anhydride (5 eq), TEA (2 eq) and Example 05-20(25 mg, 0.09 mmol, 1.0 eq) were mixed in CH₂Cl₂ and stirred at rt for 1h. Solvents were removed on the rotovap. The crude was added to aKP-Sil™ column (10 g). Alternatively a precipitate was filtered from thereaction mixture. The reaction on a 0.09 mmol scale yielded 15 mg of thetitle compound after chromatography (ESS=EtOAc, 53% yield). ¹H NMR(D6-DMSO) δ 1.72 (s, 3H), 1.95 (s, 3H), 2.48-2.50 (m, 2H), 2.85-2.87 (m,2H), 3.38-3.41 (m, 2H), 3.47-3.50 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.86(d, J=8.4 Hz, 2H). LCMS Direct Injection, m/z Calcd for C₁₇H₂₂N₃O₃;C₁₇H₂₁N₃NaO₃; C₃₄H₄₂N₆NaO₆ 316.17; 338.15; 653.31 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 316.17; 338.15; 653.31.

Example 05-22 Preparation ofN-(2-benzamidoethyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(05-22)

The title compound was prepared from Example 05-20 and phenylaceticanhydride according to the procedure of Example 05-21; 0.09 mmol scaleyielded 10 mg after chromatography (ESS=EtOAc, 29% yield). ¹H NMR(CD₃OD) δ 1.68 (s, 3H), 2.40-2.43 (m, 2H), 2.82-2.84 (m, 2H), 3.61-3.63(m, 4H), 7.33 (d, J=8.4 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.51 (t, J=7.3Hz, 1H), 7.81 (d, J=7.6 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H). LCMS DirectInjection, m/z Calcd for C₂₂H₂₄N₃O₃; C₂₂H₂₃N₃NaO₃; C₄₄H₄₆N₆NaO₆ 378.18;400.16; 777.34 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 378.18; 400.16; 777.34.

Example 05-23 Preparation of4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)piperidin-1-ium2,2,2-trifluoroacetate (05-23)

The title compound was prepared from Example 01-32 according to theprocedure of Example 05-20. ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.71 (dd,J=23.4, 10.5 Hz, 2H), 2.03 (d, J=12.9 Hz, 2H), 2.12-2.14 (m, 2H),2.50-2.52 (m, 2H), 2.96 (t, J=12.1 Hz, 2H), 3.30-3.38 (m, 2H), 3.60-3.72(m, 1H), 7.08 (d, J=8.9 Hz, 1H), 8.54 (br s, 1H), 8.77 (br s, 1H). LCMSt=1.1 min, m/z Calcd for C₁₁H₁₉N₂O; C₁₁H₁₈N₂NaO; C₂₂H₃₇N₄O₂,C₂₂H₃₆N₄NaO₂ 195.15; 217.13; 389.29; 411.27 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 195.27; 217.25; 389.36; 411.34.

Example 05-24 Preparation of tert-butyl4-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)benzylcarbamate(05-24)

The title compound was prepared from Example 02-02 and4-(N-Boc)aminomethyl-aniline according to the procedure of Example04-13; 1.0 mmol scale yielded 400 mg after chromatography (ESS=H:E(1:19), 85% yield). ¹H NMR (D6-DMSO) δ 1.40 (s, 9H), 1.48 (s, 3H),2.23-2.25 (m, 2H), 2.49-2.50 (m, 2H), 4.10 (d, J=4.6 Hz, 2H), 7.22 (d,J=7.8 Hz, 2H), 7.36-7.38 (m, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.69 (d, J=7.8Hz, 2H), 7.94 (d, J=8.3 Hz, 1H), 8.13 (s, 1H), 8.97 (s, 1H), 10.30 (s,1H). LCMS t=5.9 min, m/z Calcd for C₂₅H₂₉ClN₃O₄; C₂₅H₂₈ClN₃NaO₄;C₅₀H₅₇Cl₂N₆O₈; C₅₀H₅₆Cl₂N₆NaO₈ 470.18; 492.17; 939.36; 961.34 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 470.19; 492.13; 939.39; 961.37.

Example 05-25 Preparation of(4-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)phenyl)methanaminium2,2,2-trifluoroacetate (05-25)

The title compound was prepared from Example 05-24 according to theprocedure of Example 05-20. ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.24-2.26(m, 2H), 2.49-2.51 (m, 2H), 4.01 (d, J=5.5 Hz, 2H), 7.44 (d, J=8.4 Hz,2H), 7.49 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.3 Hz,1H), 8.09 (br s, 3H), 8.14 (s, 1H), 8.98 (s, 1H), 10.42 (s, 1H). LCMSt=5.1 min, m/z Calcd for C₂₀H₂₁ClN₃O₂; C₂₀H₂₀ClN₃NaO₂; C₄₀H₄₁Cl₂N₆O₄;C₄₀H₄₀Cl₂N₆NaO₄ 370.13; 392.11; 739.26; 761.24 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 370.13; 392.11; 739.26; 761.24.

Example 05-26 Preparation ofN-(4-(acetamidomethyl)phenyl)-3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide(05-26)

The title compound was prepared from Example 05-25 and acetic anhydrideaccording to the procedure of Example 05-21; 0.05 mmol scale yielded 10mg from precipitate (49% yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 1.87(s, 3H), 2.23-2.25 (m, 2H), 2.49-2.51 (m, 2H), 4.22 (d, J=5.7 Hz, 2H),7.23 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H),7.94 (d, J=8.2 Hz, 1H), 8.14 (s, 1H), 8.13-8.15 (m, 1H), 8.97 (s, 1H),10.31 (s, 1H). LCMS t=4.6 min, m/z Calcd for C₂₂H₂₃ClN₃O₃;C₂₂H₂₂ClN₃NaO₃; C₄₄H₄₄Cl₂N₆NaO₆ 412.14; 434.12; 845.26 [M+H]⁺; [M+Na]⁺;[2M+Na]⁺, Found 412.15; 434.09; 845.24.

Example 05-27 Preparation of tert-butyl(2-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)ethyl)carbamate(05-27)

The title compound was prepared from Example 01-36 and tert-butyl(2-aminoethyl)carbamate according to the procedure of Example 04-13; 0.5mmol scale yielded 300 mg from precipitate (71% yield). ¹H NMR (D6-DMSO)δ 1.36 (s, 9H), 1.65 (s, 3H), 1.76-1.78 (m, 2H), 2.18-2.21 (m, 4H),3.09-3.11 (s, 2H), 3.26-3.29 (m, 2H), 6.93-6.95 (m, 1H), 7.64-7.66 (m,1H), 7.72-7.75 (m, 2H), 8.08-8.10 (m, 1H), 8.58 (s, 1H). ¹³C NMR(D6-DMSO) δ 9.4, 21.6, 27.3, 28.6, 36.8, 78.1, 107.5, 126.6, 128.2,130.1, 134.2, 134.3, 137.5, 156.2, 128.9, 165.2, 195.0. LCMS t=4.9 min,m/z Calcd for C₂₁H₂₉ClN₃O₄; C₂₁H₂₈ClN₃NaO₄; C₄₂H₅₇Cl₂N₆O₈;C₄₂H₅₆Cl₂N₆NaO₈ 422.18; 444.17; 843.36; 865.34 [M+H]⁺; [M+Na]⁺; [2M+H]⁺;[2M+Na]⁺, Found 422.20; 444.18; 843.39; 865.37.

Example 05-28 Preparation ofN-(2-aminoethyl)-4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide(05-28)

The title compound was prepared from Example 05-24 according to theprocedure of Example 05-20. TFA salt was hygroscopic. Freebase wasisolated. ¹H NMR (D6-DMSO) δ 1.65 (s, 3H), 1.77-1.79 (m, 2H), 2.19-2.23(m, 4H), 2.99-3.01 (m, 2H), 3.45-3.51 (m, 2H), 7.68 (d, J=8.2 Hz, 1H),7.74-7.89 (m, 4H), 8.09-8.11 (m, 1H), 8.75 (s, 1H). ¹³C NMR (D6-DMSO) δ9.5, 21.6, 27.4, 36.8, 37.6, 39.0, 107.7, 126.6, 128.2, 130.2, 133.9,134.3, 137.6, 158.7, 165.8, 195.1. LCMS t=3.8 min, m/z Calcd forC₁₆H₂₁ClN₃O₂; C₁₆H₂₀ClN₃NaO₂; C₃₂H₄₁Cl₂N₆O₄; C₃₂H₄₀Cl₂N₆NaO₄ 322.13;344.11; 643.26; 665.24 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 322.14;344.13; 643.28; 665.26.

Example 05-29 Preparation ofN-(2-acetamidoethyl)-4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide(05-29)

The title compound was prepared from Example 05-28 and acetic anhydrideaccording to the procedure of Example 05-21; 0.10 mmol scale yielded 5mg from precipitate (14% yield). ¹H NMR (D6-DMSO) δ 1.65 (s, 3H),1.77-1.81 (m, 5H), 2.19-2.23 (m, 4H), 3.19-3.21 (m, 2H), 3.28-3.30 (m,2H), 7.65 (d, J=8.7 Hz, 1H), 7.73 (s, 2H), 7.97 (s, 1H), 8.06 (s, 1H),8.62 (s, 1H). LCMS t=4.2 min, m/z Calcd for C₁₈H₂₃ClN₃O₃;C₁₈H₂₂ClN₃NaO₃; C₃₆H₄₅Cl₂N₆O₆; C₃₆H₄₅Cl₂N₆NaO₆ 364.14; 386.12; 727.28;749.26 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 364.15; 386.14; 727.30;749.28.

Example 05-30 Preparation of tert-butyl(2-(3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-2-methylbenzamido)ethyl)carbamate(05-30)

The title compound was prepared from Example 04-95 and tert-butyl(2-aminoethyl)carbamate according to the procedure of Example 04-13; 0.5mmol scale yielded 50 mg after chromatography (ESS=EtOAc, 18% yield). ¹HNMR (D6-DMSO) δ 1.40 (s, 9H), 1.66 (s, 3H), 1.78-1.81 (m, 2H), 2.18-2.22(m, 4H), 2.26-2.28 (m, 2H), 3.09-2.12 (m, 2H), 3.24-3.28 (m, 2H), 6.87(t, J=5.4 Hz, 1H), 7.25-7.26 (m, 2H), 7.36 (t, J=4.5 Hz, 1H), 7.72 (d,J=8.1 Hz, 1H), 7.86-7.89 (m, 2H), 8.12 (s, 1H), 8.31 (t, J=5.4 Hz, 1H),10.07 (s, 1H). LCMS t=4.9 min, m/z Calcd for C₂₉H₃₆ClN₄O₅;C₂₉H₃₅ClN₄NaO₅; C₅₈H₇₁Cl₂N₈O₁₀; C₅₈H₇₀Cl₂N₈NaO₁₀ 555.24; 577.22;1109.47; 1131.45 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 555.26;577.24; 1109.51; 1131.49.

Example 05-31 Preparation of tert-butyl(2-(3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-4-methylbenzamido)ethyl)carbamate(05-31)

The title compound was prepared from Example 04-96 and tert-butyl(2-aminoethyl)carbamate according to the procedure of Example 04-13; 0.5mmol scale yielded after chromatography (ESS=EtOAc, 36% yield). ¹H NMR(D6-DMSO) δ 1.39 (s, 9H), 1.66 (s, 3H), 1.78-1.80 (m, 2H), 2.19-2.22 (m,2H), 2.26-2.28 (m, 4H), 3.09-3.11 (m, 2H), 3.27-3.30 (m, 2H), 6.91 (t,J=5.6 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.73 (d,J=8.1 Hz, 1H), 7.81 (s, 1H), 7.87-7.90 (m, 2H), 8.11 (s, 1H), 8.43 (t,J=5.3 Hz, 1H), 10.12 (s, 1H). LCMS t=5.0 min, m/z Calcd forC₂₉H₃₆ClN₄O₅; C₂₉H₃₅ClN₄NaO₅; C₅₈H₇₁Cl₂N₈O₁₀; C₅₈H₇₀Cl₂N₈NaO₁₀ 555.24;577.22; 1109.47; 1131.45 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found555.26; 577.24; 1109.50; 1131.49.

Example 05-32 Preparation of2-((3-chlorophenyl)amino)-6-oxocyclohex-1-enecarbonitrile (05-32)

The title compound was prepared from Intermediate 06 and 3-chloroanilineaccording to the procedure of Example 05-13; 1.3 mmol scale yielded 24mg after chromatography (ESS=H:E (1:1), 8% yield). ¹H NMR (D6-DMSO) δ1.82-1.85 (m, 2H), 2.26-2.29 (m, 2H), 2.58-2.60 (m, 2H), 7.26 (d, J=7.7Hz, 1H), 7.37-7.46 (m, 3H), 10.15 (s, 1H). ¹³C NMR (D6-DMSO) δ 20.6,26.7, 36.4, 86.0, 116.2, 125.4, 126.6, 127.4, 130.9, 133.5, 139.1,170.9, 193.2. LCMS t=4.6 min, m/z Calcd for C₁₃H₁₂ClN₂O; C₁₃H₁₁ClN₂NaO;C₂₆H₂₃Cl₂N₄O₂; C₂₆H₂₂Cl₂N₄NaO₂ 247.06; 269.05; 493.12; 515.10 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 247.07; 269.06; 493.14; 515.12.

Example 05-33 Preparation of4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)benzoic acid (05-33)

The title compound was prepared Intermediate 06 and3-amino-4-chlorobenzoic acid according to the procedure of Example01-01; 7.3 mmol scale yielded 0.7 g after chromatography(ESS=CH₂Cl₂:MeOH (19:1), 33% yield). ¹H NMR (D6-DMSO) δ 1.85-1.88 (m,2H), 2.28-2.30 (m, 2H), 2.50-2.58 (m, 2H), 7.72 (d, J=8.1 Hz, 1H),7.91-7.96 (m, 2H), 10.17 (s, 1H), 13.40 (br s, 1H). ¹³C NMR (D6-DMSO) δ20.3, 29.1, 36.9, 85.5, 115.6, 130.6, 130.7, 130.9, 135.3, 136.7, 166.4,193.4. LCMS t=4.1 min, m/z Calcd for C₁₄H₁₂ClN₂O₃; C₁₄H₁₁ClN₂NaO₃;C₂₈H₂₃Cl₂N₄O₆; C₂₈H₂₃Cl₂N₄NaO₆ 291.05; 313.04; 581.10; 603.08 [M+H]⁺;[M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 291.06; 313.05; 581.12; 603.10.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ R² 344-Chloro-3-((2-cyano-3-oxocyclohex-1-en- CH₃ H1-yl)amino)-N-(o-tolyl)benzamide 354-Chloro-3-((2-cyano-3-oxocyclohex-1-en- H OCH₃1-yl)amino)-N-(4-methoxyphenyl)benzamide 364-Chloro-3-((2-cyano-3-oxocyclohex-1-en- CH₃ OCH₃1-yl)amino)-N-(4-methoxy-2- methylphenyl)benzamide

Example 05-34 Preparation of4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)benzamide(05-34)

The title compound was prepared from Example 05-33 and o-toluidineaccording to the procedure of Example 04-13; 0.5 mmol scale yielded 130mg from precipitate (67% yield). ¹H NMR (D6-DMSO) δ 1.86-1.91 (m, 2H),2.23 (s, 3H), 2.29-2.34 (m, 2H), 2.50-2.60 (m, 2H), 7.19-7.24 (m, 2H),7.28-7.32 (m, 2H), 7.77 (d, J=6.8 Hz, 1H), 8.03 (s, 2H), 10.04 (s, 1H),10.21 (s, 1H). LCMS t=4.7 min, m/z Calcd for C₂₁H₁₉ClN₃O₂;C₂₁H₁₈ClN₃NaO₂; C₄₂H₃₇Cl₂N₆O₄; C₄₂H₃₆Cl₂N₆NaO₄ 380.12; 402.10; 759.23;781.21 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 380.13; 402.11; 759.25;781.24.

Example 05-35 Preparation of4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)-N-(4-methoxyphenyl)benzamide(05-35)

The title compound was prepared from Example 05-33 and p-anisidineaccording to the procedure of Example 04-13; 0.5 mmol scale yielded 113mg from precipitate (57% yield). ¹H NMR (D6-DMSO) δ 1.85-1.91 (m, 2H),2.28-2.35 (m, 2H), 2.50-2.62 (m, 2H), 3.75 (s, 3H), 6.94 (d, J=8.9 Hz,2H), 7.66 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 8.00-8.04 (m, 2H),10.23 (s, 1H). LCMS t=4.7 min, m/z Calcd for C₂₁H₁₉ClN₃O₃;C₂₁H₁₈ClN₃NaO₃; C₄₂H₃₇Cl₂N₆O₆; C₄₂H₃₆Cl₂N₆NaO₆ 396.11; 418.09; 791.22;813.20 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 396.13; 418.11; 791.24;813.23.

Example 05-36 Preparation of4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)-N-(4-methoxy-2-methylphenyl)benzamide(05-36)

The title compound was prepared from Example 05-33 and4-methoxy-2-methylaniline according to the procedure of Example 04-13;0.5 mmol scale yielded 82 mg after chromatography (ESS=H:E (1:3), 41%yield). ¹H NMR (D6-DMSO) δ 1.85-1.92 (m, 2H), 2.19 (s, 3H), 2.28-2.36(m, 2H), 2.50-2.63 (m, 2H), 3.75 (s, 3H), 6.79 (d, J=7.1 Hz, 1H), 6.86(s, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 8.03 (s, 2H),9.92 (s, 1H), 10.21 (s, 1H). ¹³C NMR (D6-DMSO) δ 18.5, 20.4, 28.9, 36.4,55.6, 85.6, 111.8, 115.8, 128.5, 129.1, 129.2, 129.5, 130.3, 134.3,135.1, 135.2, 136.0, 157.9, 163.9, 193.3. LCMS t=4.7 min, m/z Calcd forC₂₂H₂₁ClN₃O₃; C₂₂H₂₀ClN₃NaO₃; C₄₄H₄₁Cl₂N₆O₆; C₄₄H₄₀Cl₂N₆NaO₆ 410.13;432.11; 819.25; 841.23 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 410.14;432.12; 819.27; 841.26.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ R² 37N-(4-Chloro-3-((2-methyl-3-oxocyclopent- H OCH₃1-en-1-yl)amino)phenyl)-4- methoxybenzamide 38N-(4-Chloro-3-((2-methyl-3-oxocyclopent- CH₃ H1-en-1-yl)amino)phenyl)-2- methylbenzamide

Example 05-37 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-4-methoxybenzamide(05-37)

Triethylamine (0.279 mL, 2.0 mmol) was added to Example 02-14 (0.27 g,1.0 mmol) in dichloromethane (5 mL). p-Anisoyl chloride (0.142 mL, 1.05mmol) was added to the solution stirring at 0° C. After 2 h, the solventwas removed on the rotovap and the subsequent crude material was addeddirectly to a KP-Sil™ column (10 g) with products separating fromimpurities using stepwise gradients, on the Biotage®-Isolera Fourinstrument, monitoring UV Trace at 254/365 nm. The stepwise gradientutilized two solvents (hexanes and EtOAc) running from non-polar topolar steps (3:1-1:1-1:3). The 1.0 mmol scale yielded 75 mg of paleyellow microcrystals after chromatography (ESS=H:E (1:3), mp=254-257°C., 20% yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.20-2.23 (m, 2H),2.44-2.48 (m, 2H), 3.84 (s, 3H), 7.07 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8Hz, 1H), 7.69 (dd, J=8.8, 2.3 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.96 (d,J=8.7 Hz, 1H), 8.89 (s, 1H), 10.25 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.4,25.6, 32.6, 55.5, 109.4, 113.7, 118.9, 119.6, 123.7, 126.5, 129.6,129.7, 136.5, 138.8, 162.1, 165.1, 169.5, 202.3. LCMS t=5.0 min, m/zCalcd for C₂₀H₂₀ClN₂O₃; C₂₀H₁₉ClN₂NaO₃; C₄₀H₃₉Cl₂N₄O₆; C₄₀H₃₈Cl₂N₂NaO₆371.116; 393.098; 741.225; 763.207 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+,Found 371.116; 393.090; 741.217; 763.203.

Example 05-38 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzamide(05-38)

The title compound was prepared from Example 02-14 and o-toluoylchloride according to the procedure of Example 05-37; 1.0 mmol scaleyielded 65 mg of pale yellow microcrystals after chromatography (ESS=H:E(1:3), mp=230-232° C., 18% yield). ¹H NMR (D6-DMSO) δ 1.48 (s, 3H),2.20-2.22 (m, 2H), 2.38 (s, 3H), 2.44-2.48 (m, 2H), 7.29-7.33 (m, 2H),7.40 (t, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H),7.62 (dd, J=8.7, 2.0 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 8.89 (s, 1H),10.49 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.4, 19.3, 25.6, 32.6, 109.4, 118.4,118.9, 123.8, 125.7, 127.3, 129.8, 129.9, 130.6, 135.3, 136.6, 136.8,138.7, 168.1, 169.5, 202.4. LCMS t=5.1 min, m/z Calcd for C₂₀H₂₀ClN₂O₂;C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₂NaO₄ 355.121; 377.103;709.235; 731.217 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.126;377.099, 709.220; 731.208.

Example 05-39 Preparation ofN-(4-chloro-3-[(2-methyl-3-oxocyclopent-1-en-1-yl)amino]phenyl)-cyclohexanecarboxamide(05-39)

The title compound was prepared from Example 02-14 andcyclohexanecarbonyl chloride according to the procedure of Example 05-37(mp=240-242° C.). ¹H NMR (D6-DMSO) δ 1.12-1.30 (m, 3H), 1.34-1.43 (m,2H), 1.44 (s, 3H), 1.62-1.67 (m, 1H), 1.71-1.84 (m, 5H), 2.17-2.22 (m,2H), 2.26-2.34 (m, 1H), 2.41 (d, J=4.9 Hz, 2H), 7.39-7.50 (m, 2H), 7.69(s, 1H), 8.86 (s, 1H), 10.02 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.5, 25.2(2C), 25.4, 25.6, 29.0 (2C), 32.6, 44.9, 109.3, 117.8, 118.4, 123.1,129.7, 136.5, 138.9, 169.5, 174.6, 202.4. LCMS t=4.8 min, m/z Calcd forC₁₉H₂₄ClN₂O₂; C₁₉H₂₃ClN₂NaO₂; C₃₈H₄₇Cl₂N₄O₄; C₃₈H₄₆Cl₂N₄NaO₄ 347.152;369.135; 693.297; 715.279 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found347.152; 369.135; 693.297; 715.279.

Example 05-40 Preparation ofN-(4-chloro-3-[(2-methyl-3-oxocyclopent-1-en-1-yl)amino]phenyl)-naphthalene-1-carboxamide(05-40)

The title compound was prepared from Example 02-14 and 1-naphthoylchloride according to the procedure of Example 05-37 (mp=243-245° C.).¹H NMR (D6-DMSO) δ 1.49 (s, 3H), 2.19-2.25 (m, 2H), 2.47 (br s, 2H),7.56 (d, J=8.5 Hz, 1H), 7.58-7.65 (m, 3H), 7.69 (dd, J=8.5, 2.4 Hz, 1H),7.79 (d, J=7.3 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 8.02-8.05 (m, 1H), 8.10(d, J=7.3 Hz, 1H), 8.16-8.21 (m, 1H), 8.95 (s, 1H), 10.79 (s, 1H). ¹³CNMR (D6-DMSO) δ 7.5, 25.6, 32.6, 109.5, 118.6, 119.2, 124.0, 125.0,(2C), 125.7, 126.5, 127.2, 128.4, 129.6, 129.8, 130.5, 133.2, 134.2,136.7, 138.7, 167.5, 169.5, 202.4. LCMS t=4.8 min, m/z Calcd forC₂₃H₂₀ClN₂O₂; C₂₃H₁₉ClN₂NaO₂; C₄₆H₃₉Cl₂N₄O₄; C₄₆H₃₈Cl₂N₄NaO₄ 391.125;413.103; 781.235; 803.217 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found391.122; 413.103; 781.235; 803.217.

Example 05-41 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzamide(05-41)

The title compound was prepared from Example 02-15 and o-toluoylchloride according to the procedure of Example 05-37 (mp=280-283° C.).¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.15-2.20 (m, 2H), 2.32-2.36 (m, 2H),2.39 (s, 3H), 7.29-7.35 (m, 2H), 7.37-7.45 (m, 2H), 7.49 (d, J=7.3 Hz,1H), 7.66 (dd, J=8.5, 2.4 Hz, 1H), 8.07 (s, 1H), 8.87 (s, 1H), 10.55 (s,1H). ¹³C NMR (D6-DMSO) δ 7.1, 19.3, 25.2, 32.6, 108.4, 118.6, 119.9,125.7, 127.3, 129.5, 129.9, 130.6, 130.8, 131.6, 135.4, 136.7, 138.6,168.0, 170.4, 201.9. LCMS t=4.4 min, m/z Calcd for C₂₀H₂₀ClN₂O₂;C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄ 355.121; 377.103;709.235; 731.217 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 355.121;377.103; 709.235; 731.217.

Example 05-42 Preparation ofN-(2-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzamide(05-42)

The title compound was prepared from Example 02-13 and o-toluoylchloride according to the procedure of Example 05-37 (mp=118-120° C.).¹H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.15-2.22 (m, 2H), 2.40 (br s, 2H),2.45 (s, 3H), 7.25-7.35 (m, 3H), 7.40 (q, J=7.3 Hz, 2H), 7.48-7.60 (m,2H), 8.96 (s, 1H), 10.07 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.3, 19.5, 25.4,32.6, 109.1, 125.6, 125.6, 125.9, 126.8, 126.9, 127.4, 129.9, 130.6,135.6, 135.9, 136.3, 137.4, 167.9, 169.8, 202.2. LCMS t=4.4 min, m/zCalcd for C₂₀H₂₀ClN₂O₂; C₂₀H₁₉ClN₂NaO₂; C₄₀H₃₉Cl₂N₄O₄; C₄₀H₃₈Cl₂N₄NaO₄355.121; 377.103; 709.235; 731.217 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺,Found 355.121; 377.103; 709.235; 731.217.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ R² 43N-(4-Chloro-3-((2-methyl-3-oxocyclohex- H OCH₃1-en-1-yl)amino)phenyl)-4- methoxybenzamide 44N-(4-Chloro-3-((2-methyl-3-oxocyclohex- CH₃ H 1-en-1-yl)amino)phenyl)-2-methylbenzamide

Example 05-43 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-4-methoxybenzamide(05-43)

The title compound was prepared from Example 02-10 and p-anisoylchloride according to the procedure of Example 05-37; 1.0 mmol scaleyielded 60 mg after chromatography (ESS=H:E (1:3), mp=190-195° C., 16%yield). ¹H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.77-1.80 (m, 2H), 2.18-2.21(m, 2H), 2.25-2.27 (m, 2H), 3.84 (s, 3H), 7.07 (d, J=8.6 Hz, 2H), 7.49(d, J=8.7 Hz, 1H), 7.68 (dd, J=8.7, 2.1 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H),7.96 (d, J=8.6 Hz, 2H), 8.00 (s, 1H), 10.25 (s, 1H). ¹³C NMR (D6-DMSO) δ9.0, 21.2, 27.0, 36.4, 55.5, 107.1, 113.7, 118.9, 120.2, 124.5, 126.5,129.5, 129.7, 137.0, 138.9, 158.4, 162.1, 165.1, 194.5. LCMS t=5.1 min,Calcd for C₂₁H₂₂ClN₂O₃; C₂₁H₂₁ClN₂NaO₃; C₄₂H₄₂Cl₂N₂NaO₆ 385.13; 407.11;791.24 [M+H]+; [M+Na]+; [2M+Na]+, Found 385.20; 407.10; 791.22.

Example 05-44 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzamide(05-44)

The title compound was prepared from Example 02-10 and o-toluoylchloride according to the procedure of Example 05-37 (mp=199-201° C.).¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.76-1.80 (m, 2H), 2.19 (t, J=6.1 Hz,2H), 2.25 (t, J=5.5 Hz, 2H), 2.38 (s, 3H), 7.28-7.36 (m, 2H), 7.38-7.43(m, 1H), 7.44-7.56 (m, 2H), 7.62 (d, J=7.3 Hz, 1H), 7.74 (s, 1H), 8.03(s, 1H), 10.50 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.1, 19.3, 21.2, 27.0, 36.4,107.2, 118.2, 119.4, 124.5, 125.7, 127.2, 129.7, 129.9, 130.6, 135.3,136.8, 137.2, 138.7, 158.4, 168.0, 194.6. LCMS t=4.7 min, m/z Calcd forC₂₁H₂₂ClN₂O₂; C₂₁H₂₁ClN₂NaO₂; C₄₂H₄₂Cl₂N₄NaO₄ 369.137; 391.119; 759.248[M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 369.137; 391.119; 759.248.

Example 05-45 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanecarboxamide(05-45)

The title compound was prepared from Example 02-10 andcyclohexanecarbonyl chloride according to the procedure of Example 05-37(mp=192-195° C.). ¹H NMR (D6-DMSO) δ 1.14-1.22 (m, 1H), 1.22-1.30 (m,2H), 1.35-1.43 (m, 2H), 1.63 (s, 4H), 1.72-1.82 (m, 6H), 2.18 (t, J=6.1Hz, 2H), 2.22 (t, J=5.5 Hz, 2H), 2.27-2.33 (m, 1H), 7.41-7.47 (m, 2H),7.61 (s, 1H), 7.97 (s, 1H), 10.00 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.1,21.2, 25.2 (2C), 25.4, 27.0, 29.1 (2C), 36.4, 44.9, 107.1, 117.7, 118.9,123.8, 129.6, 137.1, 138.9, 158.4, 174.6, 194.6. LCMS t=4.9 min, m/zCalcd for C₂₀H₂₆ClN₂O₂; C₂₀H₂₅ClN₂NaO₂; C₄₀H₅₀Cl₂N₄NaO₄ 361.168;383.150; 743.311 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 361.168; 383.150;743.311.

Example 05-46 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-1-naphthamide(05-46)

The title compound was prepared from Example 02-10 and 1-naphthoylchloride according to the procedure of Example 05-37 (mp=245-247° C.).¹H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.77-1.83 (m, 2H), 2.20 (t, J=6.1 Hz,2H), 2.26-2.31 (m, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.58-7.65 (m, 3H), 7.69(d, J=7.3 Hz, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H),8.02-8.07 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 8.16-8.20 (m, 1H), 10.77 (s,1H). ¹³C NMR (D6-DMSO) δ 9.1, 21.2, 27.1, 36.4, 107.3, 118.4, 119.6,124.7, 125.1 (2C), 125.7, 126.5, 127.2, 128.4, 129.6, 129.8, 130.4,133.2, 134.3, 137.2, 138.7, 158.4, 167.5, 194.6. LCMS t=5.0 min, m/zCalcd for C₂₄H₂₂ClN₂O₂; C₂₄H₂₁ClN₂NaO₂; C₄₈H₄₃Cl₂N₄O₄; C₄₈H₄₂Cl₂N₄NaO₄405.136; 427.118; 809.266; 831.248 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺,Found 405.136; 427.118; 809.266; 831.248.

Example 05-47 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-1-naphthamide(05-47)

The title compound was prepared from Example 02-12 and 1-naphthoylchloride according to the procedure of Example 05-37 (mp=245-247° C.).¹H NMR (D6-DMSO) δ 1.69 (s, 3H), 1.77 (quin, J=6.4 Hz, 2H), 2.16-2.21(m, 4H), 7.35 (d, J=8.5 Hz, 1H), 7.51-7.68 (m, 3H), 7.72 (dd, J=8.5, 2.4Hz, 1H), 7.79 (d, J=7.3 Hz, 1H), 8.00-8.07 (m, 2H), 8.11 (d, J=8.5 Hz,1H), 8.14 (d, J=2.4 Hz, 1H), 8.17-8.23 (m, 1H), 10.82 (s, 1H). ¹³C NMR(D6-DMSO) δ 8.8, 21.2, 26.7, 36.3, 105.9, 118.8, 120.1, 125.1 (2C),125.7, 126.5, 127.2, 128.4, 129.6, 130.0, 130.5, 131.4, 132.3, 133.2,134.2, 138.5, 159.4, 167.5, 194.1. LCMS t=4.9 min, m/z Calcd forC₂₄H₂₂ClN₂O₂; C₂₄H₂₁ClN₂NaO₂; C₄₈H₄₃Cl₂N₄O₄; C₄₈H₄₂Cl₂N₄NaO₄ 405.136;427.118; 809.266; 831.248 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found405.136; 427.118; 809.266; 831.248.

Example 05-48 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzamide(05-48)

The title compound was prepared from Example 02-12 and o-toluoylchloride according to the procedure of Example 05-37 (mp=234-236° C.).¹H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.76 (quin, J=6.1 Hz, 2H), 2.15-2.18(m, 4H), 2.39 (s, 3H), 7.29-7.35 (m, 3H), 7.39-7.44 (m, 1H), 7.48 (d,J=7.3 Hz, 1H), 7.65 (dd, J=8.5, 2.4 Hz, 1H), 8.00 (s, 1H), 8.06 (d,J=2.4 Hz, 1H), 10.55 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.8, 19.3, 21.2, 26.7,36.3, 105.9, 118.6, 119.9, 125.7, 127.3, 129.9, 130.0, 130.6, 131.4,132.1, 135.4, 136.7, 138.5, 159.3, 168.0, 194.2. LCMS t=4.7 min, m/zCalcd for C₂₁H₂₂ClN₂O₂; C₂₁H₂₁ClN₂NaO₂; C₄₂H₄₂Cl₂N₄NaO₄ 369.137;391.119; 759.248 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 369.137; 391.119;759.248.

Example 05-49 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanecarboxamide(05-49)

The title compound was prepared from Example 02-12 andcyclohexanecarbonyl chloride according to the procedure of Example 05-37(mp=248-250° C.). ¹H NMR (D6-DMSO) δ 1.14-1.32 (m, 3H), 1.35-1.45 (m,2H), 1.66 (s, 4H), 1.71-1.82 (m, 6H), 2.11-2.17 (m, 4H), 2.28-2.35 (m,1H), 7.25 (d, J=9.8 Hz, 1H), 7.47 (dd, J=8.5, 2.4 Hz, 1H), 7.91-8.00 (m,2H), 10.06 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.7, 21.2, 25.2 (2C), 25.4,26.6, 29.0 (2C), 36.3, 44.9, 105.7, 118.0, 119.3, 130.1, 131.5 (2C),138.8, 159.4, 174.6, 194.1. LCMS t=4.8 min, m/z Calcd for C₂₀H₂₆ClN₂O₂;C₂₀H₂₅ClN₂NaO₂; C₄₀H₅₀Cl₂N₄NaO₄ 361.168; 383.150; 743.311 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 361.168; 383.150; 743.311.

Example 05-50 Preparation ofN-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzamide(05-50)

The title compound was prepared from Example 02-11 and o-toluoylchloride according to the procedure of Example 05-37. ¹H NMR (D6-DMSO) δ1.66 (s, 3H), 1.74-1.81 (m, 2H), 2.18 (t, J=6.7 Hz, 2H), 2.23 (br s,2H), 2.44 (s, 3H), 7.21 (d, J=7.3 Hz, 1H), 7.31 (d, J=7.3 Hz, 2H),7.35-7.44 (m, 2H), 7.49-7.57 (m, 2H), 8.08 (s, 1H), 10.06 (s, 1H). ¹³CNMR (D6-DMSO) δ 9.0, 19.5, 21.2, 26.9, 36.4, 106.9, 107.9, 111.2, 115.9,125.4, 125.7, 126.3, 126.9, 127.4, 129.9, 130.6, 135.6, 138.0, 158.7,167.0, 194.5. LCMS t=4.5 min, m/z Calcd for C₂₁H₂₂ClN₂O₂;C₂₁H₂₁ClN₂NaO₂; C₄₂H₄₂Cl₂N₄NaO₄ 369.137; 391.119; 759.248 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 369.137; 391.119; 759.248.

Example 05-51 Preparation ofN-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanecarboxamide(05-51)

The title compound was prepared from Example 02-11 andcyclohexanecarbonyl chloride according to the procedure of Example 05-37(mp=205-208° C.). ¹H NMR (D6-DMSO) δ 1.14-1.22 (m, 1H), 1.23-1.32 (m,2H), 1.40 (qd, J=12.4, 3.1 Hz, 2H), 1.65 (br s, 4H), 1.71-1.78 (m, 4H),1.80-1.87 (m, 2H), 2.13-2.24 (m, 4H), 2.44-2.49 (m, 1H), 7.10 (d, J=7.3Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 8.03 (s, 1H),9.42 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.4, 21.6, 25.7 (2C), 25.9, 27.3, 29.6(2C), 36.8, 44.5, 107.1, 124.3, 125.7 (2C), 127.2, 136.5, 138.2, 159.2,174.9, 194.9. LCMS t=5.3 min, m/z Calcd for C₂₀H₂₆ClN₂O₂; C₂₀H₂₅ClN₂NaO₂361.168; 383.150 [M+H]⁺; [M+Na]⁺, Found 361.157; 383.138.

Example 05-52 Preparation ofN-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-1-naphthamide(05-52)

The title compound was prepared from Example 02-11 and 1-naphthoylchloride according to the procedure of Example 05-37 (mp=178-180° C.).¹H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.73-1.84 (m, 2H), 2.19 (t, J=6.7 Hz,2H), 2.26 (br s, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.38-7.47 (m, 1H),7.56-7.67 (m, 4H), 7.79-7.91 (m, 1H), 8.03 (d, J=7.3 Hz, 1H), 8.08-8.15(m, 2H), 8.34 (d, J=7.3 Hz, 1H), 10.36 (s, 1H). ¹³C NMR (D6-DMSO) δ 9.5,21.6, 27.4, 36.8, 107.3, 125.5, 125.7, 126.0, 126.3, 126.9, 126.9,127.4, 127.5, 128.0, 128.8, 130.2, 130.9, 133.6, 134.3, 136.4, 138.5,159.2, 167.9, 195.0. LCMS t=4.7 min, m/z Calcd for C₂₄H₂₂ClN₂O₂;C₂₄H₂₁ClN₂NaO₂; C₄₈H₄₂Cl₂N₄NaO₄ 405.136; 427.118; 831.248 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 405.136; 427.118; 831.248.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ 53N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- Hyl)amino)-phenyl)methanesulfonamide 54N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- Phyl)amino)phenyl)-1-phenylmethanesulfonamide

Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-phenyl)-methanesulfonamide(05-53)

The title compound was prepared from Example 02-14 and methanesulfonylchloride according to the procedure of Example 05-37 (mp=213-215° C.).¹H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.16-2.23 (m, 2H), 2.39-2.43 (m, 2H),3.04 (s, 3H), 7.10 (dd, J=8.5, 2.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.51(d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.00 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.4,25.6, 32.6, 40.0, 109.6, 118.2, 118.8, 124.5, 130.4, 137.2, 137.8,169.3, 202.4. LCMS t=3.8 min, m/z Calcd for C₁₃H₁₆ClN₂O₃S;C₁₃H₁₅ClN₂NaO₃S; C₂₆H₃₁Cl₂N₄O₆S₂; C₂₆H₃₀Cl₂N₄NaO₆S₂ 315.057; 337.039;629.106; 651.088 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 315.057;337.039; 629.106; 651.088.

Example 05-54 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1-phenylmethanesulfonamide(05-55)

The title compound was prepared from Example 02-14 andphenylmethanesulfonyl chloride according to the procedure of Example05-37 (mp=196-198° C.). ¹H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.17-2.25 (m,2H), 2.37-2.42 (m, 2H), 4.54 (s, 2H), 7.05 (d, J=2.4 Hz, 1H), 7.07 (dd,J=8.5, 2.4 Hz, 1H), 7.21-7.28 (m, 2H), 7.31-7.38 (m, 3H), 7.48 (d, J=8.5Hz, 1H), 8.87 (s, 1H), 10.09 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.4, 25.5,32.6, 57.1, 109.5, 117.3, 117.9, 123.9, 128.3, 128.4 (2C), 129.3, 130.3,130.9 (2C), 137.1, 138.0, 169.4, 202.4. LCMS t=4.3 min, m/z Calcd forC₁₉H₂₀ClN₂O₃S; C₁₉H₁₉ClN₂NaO₃S; C₃₈H₃₉Cl₂N₄O₆S₂; C₃₈H₃₈Cl₂N₄NaO₆S₂391.088; 413.070; 781.169; 803.151 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺,Found 391.088; 413.070; 781.169; 803.151.

Example 05-55 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide(05-54)

The title compound was prepared from Example 02-14 andcyclohexanesulfonyl chloride according to the procedure of Example 05-37(mp=158-160° C.). ¹H NMR (D6-DMSO) δ 1.08-1.23 (m, 3H), 1.35-1.46 (m,5H), 1.54-1.61 (m, 1H), 1.72-1.78 (m, 2H), 2.00 (d, J=11.0 Hz, 2H),2.18-2.23 (m, 2H), 2.39-2.43 (m, 2H), 2.99-3.07 (m, 1H), 7.09-7.19 (m,2H), 7.48 (d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.02 (s, 1H). ¹³C NMR(D6-DMSO) δ 7.4, 24.3 (2C), 24.7, 25.6, 26.0 (2C), 32.6, 59.4, 109.5,117.7, 118.3, 124.1, 130.4, 137.1, 138.2, 169.2, 202.5. LCMS t=4.1 min,m/z Calcd for C₁₈H₂₄ClN₂O₃S; C₁₈H₂₃ClN₂NaO₃S; C₃₆H₄₇Cl₂N₄O₆S₂;C₃₆H₄₆Cl₂N₄NaO₆S₂ 383.120; 405.101; 765.231; 787.213 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 383.120; 405.103; 765.229; 787.213.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ 56N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- Clyl)amino)phenyl)-2-chlorobenzenesulfonamide 57N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- CH₃yl)amino)phenyl)-2-methylbenzenesulfonamide 58N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- Fyl)amino)phenyl)-2-fluorobenzenesulfonamide 59N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- CNyl)amino)phenyl)-2-cyanobenzenesulfonamide 60N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- OCH₃yl)amino)phenyl)-2-methoxybenzenesulfonamide

Example 05-56 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-phenyl)-2-chlorobenzenesulfonamide(05-56)

The title compound was prepared from Example 02-14 and2-chlorobenzene-1-sulfonyl chloride according to the procedure ofExample 05-37. ¹H NMR (D6-DMSO) δ 1.32 (s, 3H), 2.15-2.20 (m, 4H), 6.98(d, J=2.4 Hz, 1H), 7.01 (dd, J=8.5, 2.4 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H),7.51-7.55 (m, 1H), 7.63-7.67 (m, 2H), 8.05 (d, J=7.3 Hz, 1H), 8.80 (s,H), 10.90 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.2, 25.4, 32.5, 109.6, 117.9,118.5, 124.9, 127.9, 130.4, 130.7, 131.8, 132.0, 135.0, 135.9, 136.4,137.1, 169.0, 202.4. LCMS t=4.4 min, m/z Calcd for C₁₈H₁₇Cl₂N₂O₃S;C₁₈H₁₆Cl₂N₂NaO₃S; C₃₆H₃₃C₁₄N₄O₆S₂; C₃₆H₃₂C₁₄N₄NaO₆S₂ 411.033; 433.016;823.057; 843.041 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 411.033;433.016; 823.057; 843.041.

Example 05-57 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide(05-57)

The title compound was prepared from Example 02-14 and2-methylbenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=236-238° C.). ¹H NMR (D6-DMSO) δ 1.33 (s, 3H), 2.17(m, J=4.9 Hz, 4H), 2.59 (s, 3H), 6.94 (d, J=2.4 Hz, 1H), 6.99 (dd,J=8.5, 2.4 Hz, 1H), 7.33-7.45 (m, 3H), 7.52 (t, J=7.3 Hz, 1H), 7.87 (d,J=7.3 Hz, 1H), 8.80 (s, 1H), 10.68 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.2,19.7, 25.4, 32.5, 109.6, 117.6, 118.1, 124.4, 126.4, 129.4, 130.3,132.8, 133.3, 136.8, 137.0, 137.0, 137.0, 169.0, 202.4. LCMS t=5.3 min,m/z Calcd for C₁₉H₂₀ClN₂O₃S; C₁₉H₁₉ClN₂NaO₃S; C₃₈H₃₈Cl₂N₄NaO₆S₂ 391.088;413.070; 803.151 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 391.088; 413.071;803.150.

Example 05-58 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-fluorobenzenesulfonamide(05-58)

The title compound was prepared from Example 02-14 and2-fluorobenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=215-217° C.). ¹H NMR (D6-DMSO) δ 1.32 (s, 3H),2.16-2.22 (m, 4H), 7.00 (d, J=3.7 Hz, 1H), 7.03 (dd, J=8.5, 2.4 Hz, 1H),7.37 (t, J=7.9 Hz, 1H), 7.41-7.46 (m, 2H), 7.69-7.73 (m, 1H), 7.82-7.87(m, 1H), 8.82 (s, 1H), 10.88 (s, 1H). ¹³C NMR (D6-DMSO) δ 7.7, 25.9,33.0, 110.0, 117.9 (J_(CF)=21.8 Hz), 118.9, 119.5, 125.6, 126.9(J_(CF)=13.8 Hz), 130.8, 131.0, 136.8 (J_(CF)=9.2 Hz), 137.0, 137.5,158.5 (J_(CF)=254.7 Hz), 169.5, 202.9. LCMS t=4.3 min, m/z Calcd forC₁₈H₁₇ClFN₂O₃S; C₁₈H₁₆ClFN₂NaO₃S; C₃₆H₃₃Cl₂F₂N₄O₆S₂; C₃₆H₃₂C₁₂F₂N₄NaO₆S₂395.063; 417.045; 789.119; 811.101 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺,Found 395.063; 417.045; 789.119; 811.101.

Example 05-59 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-cyanobenzenesulfonamide(05-59)

The title compound was prepared from Example 02-14 and2-cyanobenzene-1-sulfonyl chloride according to the procedure of Example05-37 (mp=235-238° C.). ¹H NMR (D6-DMSO) δ 1.31 (s, 3H), 2.14-2.19 (m,2H), 2.21-2.26 (m, 2H), 6.96 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.5, 2.4 Hz,1H), 7.46 (d, J=8.5 Hz, 1H), 7.85 (t, J=7.3 Hz, 1H), 7.91 (t, J=7.3 Hz,1H), 8.04 (d, J=7.3 Hz, 1H), 8.10 (d, J=7.3 Hz, 1H), 8.82 (s, 1H), 11.06(s, 1H). ¹³C NMR (D6-DMSO) δ 7.3, 25.5, 32.5, 109.2, 109.7, 115.6,119.0, 119.5, 125.5, 129.6, 130.5, 133.8, 134.1, 136.1, 136.2, 137.2,140.5, 169.0, 202.5. LCMS t=4.3 min, m/z Calcd for C₁₉H₁₇ClN₃O₃S;C₁₉H₁₆ClN₃NaO₃S; C₃₈H₃₂Cl₂N₆NaO₆S₂ 402.068; 424.050; 825.110 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 402.068; 424.050; 825.110.

Example 05-60 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methoxybenzenesulfonamide(05-60)

The title compound was prepared from Example 02-14 and2-methoxybenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=198-200° C.). ¹H NMR (D6-DMSO) δ 1.33 (s, 3H),2.12-2.17 (m, 4H), 3.86 (s, 3H), 6.97-7.01 (m, 2H), 7.05 (t, J=7.9 Hz,1H), 7.18 (d, J=8.5 Hz, 1H), 7.34-7.41 (m, 1H), 7.58 (t, J=7.9 Hz, 1H),7.77 (d, J=7.3 Hz, 1H), 8.79 (s, 1H), 10.30 (s, 1H). ¹³C NMR (D6-DMSO) δ7.1, 25.3, 32.5, 56.2, 109.4, 112.9, 118.2, 118.7, 120.2, 124.6, 125.7,130.1, 130.4, 135.4, 136.8, 137.4, 156.3, 169.2, 202.3. LCMS t=4.2 min,m/z Calcd for C₁₉H₂₀ClN₂O₄S; C₁₉H₁₉ClN₂NaO₄S; C₃₈H₃₉Cl₂N₄O₈S₂;C₃₈H₃₈Cl₂N₄NaO₈S₂ 407.083; 429.065; 813.159; 835.141 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 407.083; 429.065; 813.159; 835.141.

EXAM- PLE TITLE COMPOUND 05-# NAME X 61N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- CH₂yl)amino)phenyl)-piperidine-1-sulfonamide 62N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1- Oyl)amino)phenyl)-morpholine-4-sulfonamide

Example 05-61 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-piperidine-1-sulfonamide(05-61)

The title compound was prepared from Example 02-14 andpiperidine-1-sulfonyl chloride according to the procedure of Example05-37 (mp=78-80° C.). ¹H NMR (D6-DMSO) δ ppm 1.36-1.48 (m, 9H),2.18-2.22 (m, 2H), 2.38-2.41 (m, 2H), 3.05-3.14 (m, 4H), 7.04-7.14 (m,2H), 7.47 (d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.14 (br s, 1H). ¹³C NMR(D6-DMSO) δ 7.3, 23.1, 24.7 (2C), 25.6, 32.6, 46.5 (2C), 109.4, 117.7,118.3, 123.7, 130.1, 136.9, 138.3, 169.2, 202.4. LCMS t=4.5 min, m/zCalcd for C₁₇H₂₃ClN₃O₃S; C₁₇H₂₂ClN₃NaO₃S; C₃₄H₄₅Cl₂N₆O₆S₂;C₃₄H₄₄Cl₂N₆NaO₆S₂ 384.114; 406.096; 767.221; 789.203 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 384.114; 406.096; 767.221; 789.203.

Example 05-62 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-morpholine-4-sulfonamide(05-62)

The title compound was prepared from Example 02-14 andmorpholine-4-sulfonyl chloride according to the procedure of Example05-37 (mp=60-67° C.). ¹H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.17-2.23 (m,2H), 2.38-2.43 (m, 2H), 3.05-3.09 (m, 4H), 3.51-3.55 (m, 4H), 7.04-7.15(m, 2H), 7.49 (d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.28 (br s, 1H). ¹³C NMR(D6-DMSO) δ ppm 7.4, 25.6, 32.6, 46.0 (2C), 65.4 (2C), 109.5, 118.1,118.6, 124.1, 130.2, 137.0, 138.0, 169.3, 202.4. LCMS t=3.9 min, m/zCalcd for C₁₆H₂₁ClN₃O₄S; C₁₆H₂₀ClN₃NaO₄S; C₃₂H₄₁Cl₂N₆O₈S₂;C₃₂H₄₀Cl₂N₆NaO₈S₂ 386.094; 408.076; 771.180; 793.162 [M+H]⁺; [M+Na]⁺;[2M+H]⁺; [2M+Na]⁺, Found 386.094; 408.076; 771.180; 793.162.

Example 05-63 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide(05-63)

The title compound was prepared from Example 02-15 and2-methylbenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=215-218° C.). ¹H NMR (D6-DMSO) δ 1.35 (s, 3H),2.09-2.15 (m, 2H), 2.22-2.27 (m, 2H), 2.59 (s, 3H), 7.03 (dd, J=8.5, 2.4Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.26 (d, J=9.8 Hz, 1H), 7.36-7.42 (m,2H), 7.53 (t, J=6.7 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 8.72 (s, 1H), 10.74(s, 1H). ¹³C NMR (D6-DMSO) δ 7.0, 19.7, 25.2, 32.5, 108.5, 117.8, 119.1,126.4, 129.4, 130.0, 131.2, 131.9, 132.8, 133.4, 136.8, 136.9, 137.0,170.1, 202.0. LCMS t=4.3 min, m/z Calcd for C₁₉H₂₀ClN₂O₃S;C₁₉H₁₉ClN₂NaO₃S; C₃₈H₃₉Cl₂N₄O₆S₂; C₃₈H₃₈Cl₂N₄NaO₆S₂ 391.088; 413.070;781.169; 803.151 [M+H]; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 391.088;413.070; 781.169; 803.151.

Example 05-64 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide(05-64)

The title compound was prepared from Example 02-15 andcyclohexanesulfonyl chloride according to the procedure of Example 05-37(mp=210-213° C.). ¹H NMR (D6-DMSO) δ 1.05-1.17 (m, 1H), 1.18-1.27 (m,2H), 1.33-1.50 (m, 5H), 1.54-1.63 (m, 1H), 1.72-1.80 (m, 2H), 1.98-2.05(m, 2H), 2.14-2.18 (m, 2H), 2.30-2.35 (m, 2H), 3.02-3.12 (m, 1H), 7.20(dd, J=8.5, 2.4 Hz, 1H), 7.34-7.38 (m, 1H), 8.81 (s, 1H), 10.09 (s, 1H).¹³C NMR (D6-DMSO) δ 7.0, 24.3 (2C), 24.7, 25.3, 26.0 (2C), 32.6, 59.6,108.4, 117.9, 119.1, 130.1, 131.4, 131.7, 138.1, 170.4, 202.0. LCMSt=4.5 min, m/z Calcd for C₁₈H₂₄ClN₂O₃S; C₁₈H₂₃ClN₂NaO₃S;C₃₆H₄₇Cl₂N₄O₆S₂; C₃₆H₄₆Cl₂N₄NaO₆S₂ 383.120; 405.101; 765.231; 787.213[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 383.120; 405.101; 765.231;787.213.

Example 05-65 Preparation ofN-(2-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide(05-65)

The title compound was prepared from Example 02-13 and2-methylbenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=75-77° C.). ¹H NMR (D6-DMSO) δ 1.32 (s, 3H), 2.10-2.13(m, 2H), 2.15-2.19 (m, 2H), 2.61 (s, 3H), 7.21 (t, J=7.3 Hz, 1H),7.19-7.24 (m, 1H), 7.26-7.31 (m, 2H), 7.39 (d, J=8.5 Hz, 1H), 7.51 (t,J=7.5 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 8.85 (s, 1H), 10.16 (s, 1H). ¹³CNMR (D6-DMSO) δ 7.1, 20.2, 25.3, 32.5, 109.0, 125.4, 126.2, 126.5,127.1, 127.3, 128.9, 132.7, 133.0, 134.4, 137.1, 137.6, 138.2, 169.6,202.2. LCMS t=4.3 min, m/z Calcd for C₁₉H₂₀ClN₂O₃S; C₁₉H₁₉ClN₂NaO₃S;C₃₈H₃₉Cl₂N₄O₆S₂; C₃₈H₃₈Cl₂N₄NaO₆S₂ 391.088; 413.070; 781.169; 803.151[M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺, Found 391.088; 413.070; 781.169;803.151.

Example 05-66 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide(05-66)

The title compound was prepared from Example 02-10 and2-methylbenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=246-248° C.). ¹H NMR (D6-DMSO) δ 1.55 (s, 3H),1.67-1.73 (m, 3H), 1.96 (t, J=5.5 Hz, 3H), 2.17 (t, J=6.7 Hz, 3H), 2.58(s, 3H), 6.85 (d, J=2.4 Hz, 1H), 6.94 (dd, J=8.5, 2.4 Hz, 1H), 7.33-7.43(m, 3H), 7.50-7.55 (m, 1H), 7.85-7.90 (m, 2H), 10.66 (s, 1H). ¹³C NMR(D6-DMSO) δ 9.0, 19.7, 21.1, 26.9, 36.4, 107.8, 117.3, 118.2, 124.7,126.4, 129.5, 130.3, 132.7, 133.3, 136.8, 137.0 (2C), 137.6, 157.8,194.7. LCMS t=4.7 min, m/z Calcd for C₂₀H₂₂ClN₂O₃S; C₂₀H₂₁ClN₂NaO₃S;C₄₀H₄₂Cl₂N₄NaO₆S₂ 405.104; 427.086; 831.182 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺,Found 405.104; 427.086; 831.182.

Example 05-67 Preparation ofN-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide(05-67)

The title compound was prepared from Example 02-10 andcyclohexanesulfonyl chloride according to the procedure of Example 05-37(mp=215-217° C.). ¹H NMR (D6-DMSO) δ 1.08-1.15 (m, 1H), 1.16-1.24 (m,2H), 1.39 (qd, J=12.4, 3.1 Hz, 2H), 1.58 (d, J=13.4 Hz, 1H), 1.62 (s,3H), 1.72-1.79 (m, 4H), 1.96-2.03 (m, 2H), 2.17-2.24 (m, 4H), 2.97-3.06(m, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.5, 2.4 Hz, 1H), 7.46 (d,J=8.5 Hz, 1H), 7.98 (s, 1H), 9.98-10.02 (m, 1H). ¹³C NMR (D6-DMSO) δ9.1, 21.1, 24.4 (2C), 24.7, 26.0 (2C), 27.1, 36.4, 59.4, 107.7, 117.3,118.5, 124.5, 130.3, 137.7, 138.2, 158.1, 194.7. LCMS t=4.7 min, m/zCalcd for C₁₉H₂₆ClN₂O₃S; C₁₉H₂₅ClN₂NaO₃S; C₃₈H₅₀Cl₂N₄NaO₆S₂ 397.135;419.117; 815.245 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 397.135; 419.117;815.244.

Example 05-68 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide(05-68)

The title compound was prepared from Example 02-12 and2-methylbenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=248-250° C.). ¹H NMR (D6-DMSO) δ 1.59 (s, 3H), 1.70(quin, J=6.1 Hz, 2H), 2.05 (t, J=5.5 Hz, 2H), 2.12 (t, J=6.1 Hz, 2H),2.59 (s, 3H), 7.03 (dd, J=8.5, 2.4 Hz, 1H), 7.15-7.21 (m, 2H), 7.36-7.44(m, 2H), 7.53 (t, J=6.7 Hz, 1H), 7.84 (s, 1H), 7.90 (d, J=7.3 Hz, 1H),10.74 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.7, 19.7, 21.1, 26.6, 36.3, 106.0,117.7, 119.1, 126.4, 129.4, 130.5, 131.8, 132.3, 132.3, 132.8, 133.4,136.8, 137.1, 159.0, 194.2. LCMS t=4.6 min, m/z Calcd for C₂₀H₂₂ClN₂O₃S;C₂₀H₂₁ClN₂NaO₃S; C₄₀H₄₂Cl₂N₄NaO₆S₂ 405.104; 427.086; 831.182 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 405.104; 427.086; 831.182.

Example 05-69 Preparation ofN-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide(05-69)

The title compound was prepared from Example 02-12 andcyclohexanesulfonyl chloride according to the procedure of Example 05-37(mp=230-232° C.). ¹H NMR (D6-DMSO) δ 1.07-1.17 (m, 1H), 1.18-1.27 (m,2H), 1.36-1.46 (m, 2H), 1.56-1.62 (m, 1H), 1.65 (s, 3H), 1.73-1.79 (m,4H), 2.02 (d, J=12.2 Hz, 2H), 2.13-2.17 (m, 4H), 3.03-3.11 (m, 1H), 7.19(dd, J=8.5, 2.4 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H),7.93 (s, 1H), 10.08 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.7, 21.2, 24.3 (2C),24.7, 26.0 (2C), 26.6, 36.3, 59.5, 105.9, 117.9, 119.2, 130.6, 132.0,132.1, 138.0, 159.2, 194.1. LCMS t=4.3 min, m/z Calcd for C₁₉H₂₆ClN₂O₃S;C₃₈H₅₀Cl₂N₄NaO₆S₂ 397.135; 815.245 [M+H]⁺; [2M+Na]⁺, Found 397.134;815.245.

Example 05-70 Preparation ofN-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide(05-70)

The title compound was prepared from Example 02-11 and2-methylbenzene-1-sulfonyl chloride according to the procedure ofExample 05-37 (mp=185-187° C.). ¹H NMR (D6-DMSO) δ 1.56 (s, 3H),1.62-1.71 (m, 2H), 1.92 (t, J=5.5 Hz, 2H), 2.13 (t, J=6.1 Hz, 2H), 2.61(s, 3H), 7.10 (d, J=7.3 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.24-7.31 (m,2H), 7.38 (d, J=7.3 Hz, 1H), 7.50 (t, J=7.2 Hz, 2H), 7.62 (d, J=8.5 Hz,1H), 7.96 (s, 1H), 10.13 (br s, 1H). ¹³C NMR (D6-DMSO) δ 9.4, 20.7,21.5, 27.1, 36.8, 107.3, 120.0, 125.6, 126.5, 127.2, 127.5, 128.2,129.3, 133.1, 133.4, 135.0, 137.6, 138.6, 159.0, 194.9. LCMS t=4.5 min,m/z Calcd for C₂₀H₂₂ClN₂O₃S; C₂₀H₂₁ClN₂NaO₃S; 405.104; 427.086; 831.182[M+H]⁺; [M+Na]⁺; Found 405.104; 427.086.

Example 05-71 Preparation ofN-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide(05-71)

The title compound was prepared from Example 02-11 andcyclohexanesulfonyl chloride according to the procedure of Example05-37. ¹H NMR (D6-DMSO) δ 1.08-1.17 (m, 1H), 1.19-1.29 (m, 2H), 1.41(qd, J=12.4, 3.1 Hz, 2H), 1.57-1.67 (m, 4H), 1.73-1.80 (m, 4H),2.06-2.12 (m, 2H), 2.13-2.22 (m, 4H), 2.96-3.06 (m, 1H), 7.15 (d, J=7.3Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.39 (d, J=9.8 Hz, 1H), 8.04 (s, 1H),9.48 (br s, 1H). ¹³C NMR (D6-DMSO) δ 9.0, 21.2, 24.5 (2C), 24.8, 26.2(2C), 26.9, 36.4, 61.3, 104.7, 114.9, 115.4, 119.7, 127.1, 138.1, 143.9,158.5, 194.5. LCMS t=4.5 min, m/z Calcd for C₁₉H₂₆ClN₂O₃S;C₁₉H₂₅ClN₂NaO₃S; C₃₈H₅₀Cl₂N₄NaO₆S₂ 397.135; 419.117; 815.245 [M+H];[M+Na]⁺; [2M+Na]⁺, Found 397.135; 419.117; 815.245.

Example 05-72 Preparation of3-((2-chloro-5-((2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone(05-72)

Acetic acid (0.4 mL) was added to Example 02-10 (0.3 g, 1.20 mmol) and2-methylbenzaldehyde (0.25 g, 2.04 mmol) stirring in MeOH (8 mL). Afterstirring for 1 h, borane-2-methylpyridine (0.17 g, 1.59 mmol) was addedto the mixture. The mixture was stirred for 18 h. The crude wasconcentrated under vacuum and purified by HPLC to afford the titlecompound (0.13 g, 23% yield, mp=158-160° C.). ¹H NMR (D6-DMSO) δ 1.63(s, 3H), 1.70 (quin, J=6.4 Hz, 2H), 2.11-2.14 (m, 4H), 2.31 (s, 3H),4.21 (d, J=4.9 Hz, 2H), 6.40 (t, J=5.5 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H),6.53 (dd, J=9.2, 3.1 Hz, 1H), 7.08-7.22 (m, 4H), 7.23 (d, J=6.1 Hz, 1H),7.84 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.7, 18.6, 21.2, 26.6, 36.3, 44.6,105.9, 111.6, 112.2, 116.7, 125.7, 126.8, 127.2, 129.5, 130.1, 135.9,137.0, 137.0, 148.4, 159.2, 194.0. LCMS t=5.3 min, m/z Calcd forC₂₁H₂₄ClN₂O; C₂₁H₂₃ClN₂NaO; C₄₂H₄₆Cl₂N₄NaO₂ 355.158; 377.139; 731.290[M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 355.158; 377.139; 731.290.

Example 05-73 Preparation of3-((2-chloro-5-((2-methylphenethyl)amino)phenyl)amino)-2-methylcyclohex-2-enone(05-73)

The title compound was prepared from Example 02-10 and2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72(mp=85-87° C.). ¹H NMR (D6-DMSO) δ 1.65 (s, 3H), 1.75 (quin, J=6.1 Hz,2H), 2.15 (t, J=6.1 Hz, 2H), 2.21 (t, J=5.5 Hz, 2H), 2.28 (s, 3H), 2.81(t, J=7.9 Hz, 2H), 3.15-3.26 (m, 2H), 6.05 (t, J=5.5 Hz, 1H), 6.48 (d,J=2.4 Hz, 1H), 6.53 (dd, J=8.5, 2.4 Hz, 1H), 6.89-7.37 (m, 5H), 7.87 (s,1H). ¹³C NMR (D6-DMSO) δ 8.8, 19.0, 21.3, 26.7, 32.1, 36.4, 43.3, 105.8,111.5, 112.2, 116.7, 125.9, 126.2, 129.1, 129.6, 130.0, 135.8, 137.2,137.8, 148.3, 159.3, 194.1. LCMS t=5.5 min, m/z Calcd for C₂₂H₂₆ClN₂O;C₂₂H₂₅ClN₂NaO; C₄₄H₅₀Cl₂N₄NaO₂ 369.173; 391.155; 759.321 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 369.173; 391.155; 759.321.

EXAM- PLE TITLE COMPOUND 05-# NAME R¹ R² 74 3-((2-Chloro-5-((2- F Hfluorobenzyl)amino)phenyl)amino)-2- methylcyclohex-2-enone 753-((2-Chloro-5-((3-fluoro-2- CH₃ F methylbenzyl)amino)phenyl)amino)-2-methylcyclo-hex-2-enone

Example 05-74 Preparation of3-((2-chloro-5-((2-fluorobenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone(05-74)

The title compound was prepared from Example 02-10 and2-fluorobenzaldehyde according to the procedure of Example 05-72(mp=103-105° C.). ¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.70 (quin, J=6.4 Hz,2H), 2.09-2.15 (m, 4H), 4.31 (d, J=6.1 Hz, 2H), 6.45 (d, J=2.4 Hz, 1H),6.50-6.56 (m, 2H), 7.09-7.25 (m, 3H), 7.26-7.33 (m, 1H), 7.37 (t, J=7.9Hz, 1H), 7.83 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.7, 21.2, 26.6, 36.3, 40.0,106.0, 111.7, 112.3, 115.2 (J_(CF)=20.7 Hz), 117.1, 124.3, 126.1(J_(CF)=14.9 Hz), 128.9 (J_(CF)=6.9 Hz), 129.4 (J_(CF)=4.6 Hz), 129.6,137.1, 147.9, 159.1, 160.4 (J_(CF)=244.4 Hz), 194.1. LCMS t=5.1 min, m/zCalcd for C₂₀H₂₁ClFN₂O; C₂₀H₂₀ClFN₂NaO; 359.13; 381.12; [M+H]⁺; [M+Na]⁺,Found 359.13; 381.10.

Example 05-75 Preparation of3-((2-chloro-5-((3-fluoro-2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone(05-75)

The title compound was prepared from Example 02-10 and2-fluoro-3-methylbenzaldehyde according to the procedure of Example05-72 (mp=160-162° C.). ¹H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.71 (quin,J=6.4 Hz, 2H), 2.10-2.16 (m, 4H), 2.21 (s, 3H), 4.25 (d, J=6.1 Hz, 2H),6.42-6.47 (m, 2H), 6.52 (dd, J=8.5, 2.4 Hz, 1H), 7.03-7.07 (m, 1H), 7.09(d, J=8.5 Hz, 1H), 7.14-7.20 (m, 2H), 7.83 (s, 1H). ¹³C NMR (D6-DMSO) δ9.2, 10.2 (J_(CF)=5.7 Hz), 21.7, 27.1, 36.8, 44.8, 106.4, 112.1, 112.7,113.9 (J_(CF)=24.1 Hz), 117.4, 123.1 (J_(CF)=16.1 Hz), 123.5, 127.2(J_(CF)=9.2 Hz), 130.1, 137.5, 140.5, 148.6, 159.6, 161.1 (J_(CF)=242.1Hz), 194.6. LCMS t=5.2 min, m/z Calcd for C₂₁H₂₃ClFN₂O; C₂₁H₂₂ClFN₂NaO;C₄₂H₄₄Cl₂F₂N₄NaO₂ 373.148; 395.130; 767.271 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺,Found 373.148; 395.130; 767.271.

Example 05-76 Preparation of3-((2-chloro-4-((2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone(05-76)

The title compound was prepared from Example 02-12 and2-methylbenzaldehyde according to the procedure of Example 05-72(mp=220-221° C.). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.71 (quin, J=6.4 Hz,2H), 2.07 (t, J=6.1 Hz, 2H), 2.11 (t, J=6.7 Hz, 2H), 2.32 (s, 3H), 4.22(d, J=4.9 Hz, 2H), 6.46 (t, J=5.5 Hz, 1H), 6.56 (dd, J=8.5, 2.4 Hz, 1H),6.71 (d, J=2.4 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 7.11-7.22 (m, 3H), 7.25(d, J=7.3 Hz, 1H), 7.78 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.4, 18.6, 21.2,26.3, 36.2, 44.7, 104.2, 111.1, 111.6, 124.3, 125.7, 126.9, 127.3,130.1, 130.9, 132.8, 136.0, 136.8, 148.8, 160.7, 193.5. LCMS t=5.2 min,m/z Calcd for C₂₁H₂₄ClN₂O; C₂₁H₂₃ClN₂NaO; C₄₂H₄₆Cl₂N₄NaO₂ 355.158;377.139; 731.290 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 355.156; 377.139;731.290.

Example 05-77 Preparation of3-((2-chloro-4-((2-methylphenethyl)amino)phenyl)amino)-2-methyl-cyclohex-2-enone(05-77)

The title compound was prepared from Example 02-12 and2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72(mp=160-162° C.). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.72 (quin, J=6.1 Hz,2H), 2.06-2.10 (m, 2H), 2.12 (t, J=6.1 Hz, 2H), 2.30 (s, 3H), 2.83 (t,J=7.3 Hz, 2H), 3.19-3.26 (m, 2H), 6.16 (t, J=5.5 Hz, 1H), 6.57 (dd,J=8.5, 2.4 Hz, 1H), 6.66-6.73 (m, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.08-7.18(m, 3H), 7.21 (d, J=8.5 Hz, 1H), 7.80 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.4,19.0, 21.2, 26.3, 32.1, 36.2, 43.2, 104.3, 111.0, 111.4, 124.2, 125.9,126.2, 129.1, 130.0, 130.9, 132.9, 135.8, 137.7, 148.7, 160.7, 193.5.LCMS t=5.4 min, m/z Calcd for C₂₂H₂₆ClN₂O; C₂₂H₂₅ClN₂NaO;C₄₄H₅₀Cl₂N₄NaO₂ 369.173; 391.155; 759.321 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺,Found 369.173; 391.155; 759.321.

Example 05-78 Preparation of3-((2-chloro-3-((2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone(05-78)

The title compound was prepared from Example 02-11 and2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72(mp=132-135° C.). ¹H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.75 (quin, J=6.1 Hz,2H), 2.16 (t, J=6.7 Hz, 2H), 2.21 (t, J=6.1 Hz, 2H), 2.34 (s, 3H), 4.38(d, J=6.1 Hz, 2H), 6.07 (t, J=6.1 Hz, 1H), 6.39 (d, J=8.5 Hz, 1H), 6.51(d, J=7.3 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 7.07-7.24 (m, 4H), 7.91 (s,1H). ¹³C NMR (D6-DMSO) δ 8.7, 18.6, 21.3, 26.7, 36.4, 44.3, 105.8,109.2, 115.9, 116.1, 125.7, 126.1, 126.5, 127.2, 130.1, 135.4, 136.8,137.3, 144.9, 159.2, 194.1. LCMS t=5.1 min, m/z Calcd for C₂₁H₂₄ClN₂O;C₂₁H₂₃ClN₂NaO 355.158; 377.139; [M+H]⁺; [M+Na]⁺, Found 355.152; 377.133.

Example 05-79 Preparation of3-((2-chloro-3-((2-methylphenethyl)amino)phenyl)amino)-2-methylcyclohex-2-enone(05-79)

The title compound was prepared from Example 02-11 and2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72(mp=157-160° C.). ¹H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.74 (quin, J=6.4 Hz,2H), 2.14-2.20 (m, 4H), 2.32 (s, 3H), 2.86-2.91 (m, 2H), 3.34-3.36 (m,2H), 5.51 (t, J=5.5 Hz, 1H), 6.53 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.5 Hz,1H), 7.09-7.17 (m, 4H), 7.20 (d, J=7.3 Hz, 1H), 7.92 (s, 1H). ¹³C NMR(D6-DMSO) δ 8.8, 19.0, 21.2, 26.6, 32.1, 36.3, 43.3, 105.8, 108.7,116.0, 116.1, 125.9, 126.2, 127.4, 129.3, 130.0, 136.0, 137.4, 137.6,144.9, 159.2, 194.1. LCMS t=5.5 min, m/z Calcd for C₂₂H₂₆ClN₂O;C₂₂H₂₅ClN₂NaO; C₄₄H₅₀Cl₂N₄NaO₂ 369.173; 391.155; 759.321 [M+H]⁺;[M+Na]⁺; [2M+Na]⁺, Found 369.175; 391.155; 759.321.

Example 05-80 Preparation of3-((2-chloro-3-(o-tolylamino)phenyl)amino)-2-methylcyclohex-2-enone(05-80)

Example 02-11 (0.5 g, 2.00 mmol), 1-bromo-2-methylbenzene (0.408 g, 2.39mmol), palladium acetate (0.045 g, 0.20 mmol), BINAP (0.249 g, 0.40mmol), cesium carbonate (1.30 g, 3.99 mmol) and toluene (10 mL) werecombined in a sealed flask and heated at 130° C., for 18 h. At rt, themixture was filtered and the filtrate was diluted with EtOAc (30 mL),washed with brine (3×10 mL), dried with Na₂SO₄. The crude was purifiedby HPLC to afford the title compound (yellow microcrystal, 15 mg, 2.2%).¹H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.73-1.82 (m, 2H), 2.14 (s, 3H), 2.18(t, J=6.7 Hz, 2H), 2.25 (t, J=6.1 Hz, 2H), 6.42 (d, J=7.3 Hz, 1H), 6.70(d, J=6.1 Hz, 1H), 7.09 (t, J=7.9 Hz, 3H), 7.20 (t, J=7.9 Hz, 1H), 7.23(s, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.97 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.8,17.7, 21.3, 26.8, 36.4, 106.2, 112.9, 118.4, 118.7, 124.4, 124.5, 126.8,127.1, 130.9, 132.6, 137.9, 140.0, 143.3, 159.0, 194.2. LCMS t=5.1 min,m/z Calcd for C₂₀H₂₂ClN₂O; C₂₀H₂₁ClN₂NaO; C₄₀H₄₃Cl₂N₄O₂; 341.142;363.124; 703.258 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 341.146; 363.124;703.258.

Example 05-81 Preparation of3-((2-chloro-5-(o-tolylamino)phenyl)amino)-2-methylcyclohex-2-enone(05-81)

The title compound was prepared from Example 02-10 according to theprocedure of Example 05-80 (mp=165-168° C.). ¹H NMR (D6-DMSO) δ 1.64 (s,3H), 1.76 (quin, J=6.1 Hz, 2H), 2.14-2.17 (m, 2H), 2.19 (s, 3H), 2.22(t, J=5.5 Hz, 2H), 6.66 (d, J=2.4 Hz, 1H), 6.71-6.76 (m, 1H), 6.98 (t,J=7.9 Hz, 1H), 7.13-7.20 (m, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.28 (d, J=8.5Hz, 1H), 7.70 (s, 1H), 7.90 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.8, 17.9,21.2, 26.8, 36.4, 106.4, 114.2, 115.1, 119.3, 121.3, 123.1, 126.7,129.9, 130.7, 131.1, 137.4, 140.2, 145.1, 158.9, 194.3. LCMS t=5.0 min,m/z Calcd for C₂₀H₂₂ClN₂O; C₂₀H₂₁ClN₂NaO; C₄₀H₄₂Cl₂N₄NaO₂ 341.142;363.124; 703.258 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺, Found 341.142; 363.124;703.258.

Example 05-82 Preparation of3-((2-chloro-4-(o-tolylamino)phenyl)amino)-2-methylcyclohex-2-enone(05-82)

The title compound was prepared from Example 02-12 according to theprocedure of Example 05-80 (mp=68-70° C.). ¹H NMR (D6-DMSO) δ 1.67 (s,3H), 1.74 (quin, J=6.4 Hz, 2H), 2.10-2.16 (m, 4H), 2.19 (s, 3H), 6.77(dd, J=8.5, 2.4 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.98-7.03 (m, 1H), 7.12(d, J=8.5 Hz, 1H), 7.15-7.21 (m, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.80 (s,1H), 7.85 (s, 1H). ¹³C NMR (D6-DMSO) δ 8.5, 17.9, 21.3, 26.4, 36.3,104.7, 113.7, 114.7, 114.7, 121.7, 123.4, 126.7, 130.9, 131.0, 131.1,132.6, 139.9, 145.5, 160.3, 193.7. LCMS t=5.1 min, m/z Calcd forC₂₀H₂₂ClN₂O; C₄₀H₄₂Cl₂N₄NaO₂ 341.142; 703.258 [M+H]⁺; [2M+Na]⁺, Found341.142; 703.261.

Example 05-83 Preparation of(Z)-4-((4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-amino)-4-oxobut-2-enoicacid (05-83)

Example 02-10 (0.5 g, 2.0 mmol) and furan-2,5-dione (0.196 g, 2.0 mmol)were stirred in THF (10 mL) at rt, for 18 h. The solvent was removedunder vacuum and purified by HPLC to afford the title compound (0.19 g,27.3% yield, mp=182-185° C.). ¹H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.73-1.81(m, 2H), 2.19 (t, J=6.1 Hz, 2H), 2.23 (t, J=5.5 Hz, 2H), 6.31 (d, J=12.2Hz, 1H), 6.40 (d, J=12.2 Hz, 1H), 7.41-7.52 (m, 2H), 7.61 (d, J=2.4 Hz,1H), 8.02 (s, 1H), 10.89 (br s, 1H), 12.73 (br s, 1H). ¹³C NMR (D6-DMSO)δ 9.1, 21.2, 27.0, 36.4, 107.2, 118.0, 119.2, 124.6, 129.8, 131.0,131.4, 137.3, 138.2, 158.3, 163.5, 167.0, 194.6. LCMS t=3.9 min, m/zCalcd for C₁₇H₁₈ClN₂O₄; C₁₇H₁₇ClN₂NaO₄; C₃₄H₃₅Cl₂N₄O₈; C₃₄H₃₄Cl₂N₄NaO₈349.096; 371.078; 697.183; 719.165 [M+H]⁺; [M+Na]⁺; [2M+H]⁺; [2M+Na]⁺,Found 349.096; 371.075; 697.176; 719.166.

Example 05-84 Preparation of(Z)-4-((3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-amino)-4-oxobut-2-enoicacid (05-84)

The title compound was prepared from Example 02-12 according to theprocedure of Example 05-83 (mp=200-202° C.). ¹H NMR (D6-DMSO) δ 1.66 (s,3H), 1.72-1.77 (m, 2H), 2.10-2.19 (m, 4H), 6.33 (d, J=12.2 Hz, 1H), 6.47(d, J=12.2 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.49 (dd, J=8.5, 2.4 Hz,1H), 7.94 (d, J=2.4 Hz, 1H), 7.97 (s, 1H), 10.58 (br s, 1H), 12.92 (brs, 1H). ¹³C NMR (D6-DMSO) δ 8.8, 21.2, 26.7, 36.3, 106.0, 118.4, 119.7,130.0, 130.2, 131.4, 131.6, 132.3, 137.9, 159.2, 163.5, 166.9, 194.2.LCMS t=3.9 min, m/z Calcd for C₁₇H₁₈ClN₂O₄; C₁₇H₁₇ClN₂NaO₄;C₃₄H₃₄Cl₂N₄NaO₈ 349.096; 371.078; 719.165 [M+H]⁺; [M+Na]⁺; [2M+Na]⁺,Found 349.096; 371.078; 719.164.

Example 05-85 Preparation of(Z)-4-((2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-amino)-4-oxobut-2-enoicacid (05-85)

Example 02-11 (0.2 g, 0.8 mmol), furan-2,5-dione (0.392 g, 4.0 mmol) andAcOH (1 mL) were stirred in THF (10 mL) was stirred at rt, for 18 h. Thesolvent was removed under vacuum and purified by HPLC to afford thetitle compound (0.14 g, 50.3% yield). ¹H NMR (D6-DMSO) δ 1.67 (s, 3H),1.73-1.79 (m, 2H), 2.15-2.22 (m, 4H), 4.06 (br s, 0.5H), 5.77 (d, J=13.4Hz, 1H), 6.19 (d, J=13.4 Hz, 1H), 7.04 (d, J=7.3 Hz, 1H), 7.12-7.33 (m,3H), 7.80 (d, J=7.3 Hz, 1H), 8.01 (s, 0.5H). LCMS t=3.6 min, m/z Calcdfor C₁₇H₁₈ClN₂O₄; C₁₇H₁₇ClN₂NaO₄ 349.096; 371.078 [M+H]⁺; [M+Na]⁺, Found349.096; 371.078.

Examples 06-01 to 06-011

Example 06-# TITLE COMPOUND NAME R 013-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone 022-methyl-3-((3-(1-phenyl-1H-1,2,3-triazol-4- Phyl)phenyl)amino)cyclopent-2-enone 033-((3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)- 4-OCH₃Ph2-methylcyclopent-2-enone 043-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂Phmethylcyclopent-2-enone 052-methyl-3-((3-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4- CH₂ 4-yl)phenyl)amino)cyclopent-2-enone CH₃Ph 063-((3-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂4-FPh methylcyclopent-2-enone 073-((3-(1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂3-FPh methylcyclopent-2-enone 083-((3-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂2-FPh methylcyclopent-2-enone 094-((4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H- CH₂ 4-1,2,3-triazol-1-yl)methyl)benzamide CONH₂Ph 102-methyl-3-((3-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4- CH₂ 2-yl)phenyl)amino)cyclopent-2-enone CH₃Ph 112-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-1,2,3-triazol-4- CH₂ 3-yl)phenyl)amino)cyclopent-2-enone Pyridyl

Example 06-01 Preparation of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (06-01)

2-methylcyclopentane-1,3-dione (0.112 g, 0.996 mmol), 3-ethynylaniline(0.112 mL, 0.996 mmol), and acetic acid (0.029 mL, 0.499 mmol), wereadded to a 0.5-2 mL Biotage® microwave vial. The biotage Intiator®microwave reactor was programmed to heat at 160° C. for 30 min. Thereaction mixture was dissolved in dichloromethane, concentrated invacuo, purified by combiflash (SiO₂, 7% methanol in dichloromethane),triturated with ethylacetate, and filtered to give3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.046 g, 22%) as ayellow solid. ¹H NMR (600 MHz, MeOD) δ 7.37-7.35 (2H, m), 7.31-7.27 (2H,m), 3.55-3.54 (1H, m), 2.72 (2H, bs), 2.40-2.38 (2H, m), 1.66 (3H, s);¹³C NMR (150 MHz, MeOD) δ 205.3, 173.7, 139.6, 129.2, 128.7, 126.9,124.2, 123.5, 110.2, 82.4, 78.2, 32.7, 25.8, 5.6; LCMS m/z 212.1827([M+H⁺], C₁₄H₁₄NO requires 212.1070).

General synthesis procedure for3-((3-(1-substituted-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enones—06-02to 06-011. To a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (1 Eq) andsubstituted azide (2 Eq) in a mixture of water and tert-butyl alcohol(1:1, 0.071 mmol/mL) was added sodium ascorbate (0.01 Eq, 1 M solutionin water), followed by copper (II) sulfate pentahydrate (0.01 Eq). Theheterogeneous mixture was stirred at RT for the specified time. Thereaction mixture was diluted with water and cooled in an ice bath. Theprecipitate formed was filtered and washed with water. The precipitatewas then dissolved in dichloromethane, dried (Na₂SO₄), concentrated, andpurified as specified.

Example 06-02 Preparation of2-methyl-3-((3-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-02)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.015 g, 0.071mmol) and azidobenzene (0.017 g, 0.142 mmol), sodium ascorbate, andcopper (II) sulfate pentahydrate in a mixture of water and tert-butylalcohol were stirred at RT for 14 h. Purification was done by washingthe solid precipitate with dichloromethane to afford2-methyl-3-((3-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.022 g, 96%) as a yellow solid. ¹H NMR (600 MHz, MeOD) δ 8.97 (1H, s),7.92 (2H, d, J=7.8 Hz), 7.84 (1H, bs), 7.78 (1H, d, J=7.2 Hz), 7.61 (2H,t, J=7.8 Hz), 7.53-7.49 (2H, m), 7.28 (1H, d, J=7.8 Hz), 2.80 (2H, bs),2.41 (2H, bs), 1.70 (3H, s); ¹³C NMR (150 MHz, MeOD) δ 205.2, 174.0,140.1, 137.2, 131.4, 129.8, 128.9, 123.8, 122.6, 120.9, 120.2, 119.5,33.0, 29.5, 25.8, 5.7; LCMS m/z 331.2967 ([M+H⁺], C₂₀H₁₉N₄O requires331.1554).

Example 06-03 Preparation of3-((3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-03)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.050 g, 0.236mmol) and 1-azido-4-methoxybenzene (0.070 g, 0.473 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 15 h. Purification wasdone by combiflash (SiO₂, 90% ethylacetate in hexanes) to yield3-((3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.015 g, 18%) as a white solid. ¹H NMR (600 MHz, MeOD) δ 8.87 (1H, s),7.83-7.76 (4H, m), 7.52-7.49 (1H, m), 7.29 (1H, dd, J=1.8, 7.8 Hz),7.15-7.13 (1H, m), 3.89 (3H, s), 2.82-2.80 (2H, m), 2.43-2.41 (2H, m),1.71 (3H, s); LCMS m/z 361.3447 ([M+H⁺], C₂₁H₂₁N₄O₂ requires 361.1660).

Example 06-04 Preparation of3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-04)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.050 g, 0.236mmol) and (azidomethyl)benzene (0.063 g, 0.472 mmol), sodium ascorbate,and copper (II) sulfate pentahydrate in a mixture of water andtert-butyl alcohol were stirred at RT for 14 h. Purification was done bycombiflash (SiO₂, 2%-5% methanol in dichloromethane) to yield3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.040 g, 49%) as a white solid. ¹H NMR (600 MHz, MeOD) δ 8.36 (1H, s),7.70 (1H, s), 7.62 (1H, d, J=7.8 Hz), 7.43-7.40 (1H, m), 7.35-7.32 (4H,m), 7.21 (1H, d, J=7.8 Hz), 5.61 (2H, d, J=1.8 Hz), 2.72 (2H, bs),2.36-2.35 (2H, m), 1.67 (3H, s); ¹³C NMR (150 MHz, MeOD) δ 205.1, 173.9,147.2, 140.0, 135.5, 131.6, 129.7, 128.8, 128.4, 127.9, 123.4, 122.4,121.4, 120.6, 53.8, 32.7, 25.8, 5.7; LCMS m/z 345.3331 ([M+H⁺],C₂₁H₂₁N₄O requires 345.1710).

Example 06-05 Preparation of2-methyl-3-((3-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-05)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355mmol) and 1-(azidomethyl)-4-methylbenzene (0.104 g, 0.710 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 11 h. Purification wasdone by combiflash (SiO₂, 3%-5% methanol in dichloromethane) to yield2-methyl-3-((3-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.103 g, 81%) as a white solid. ¹H NMR (600 MHz, MeOD) δ 8.33 (1H, bs),7.70 (1H, s), 7.63 (1H, d, J=7.8 Hz), 7.43 (1H, t, J=7.8 Hz), 7.26-7.18(5H, m), 5.57 (2H, s), 2.74 (2H, bs), 2.38-2.37 (2H, m), 2.31 (3H, s),1.68 (3H, s); ¹³C NMR (150 MHz, MeOD) δ205.1, 174.0, 147.2, 140.0,138.5, 132.4, 131.6, 129.7, 129.4, 127.9, 123.5, 122.4, 121.3, 120.7,110.0, 53.7, 32.7, 25.8, 19.9, 5.7; LCMS m/z 359.4512 ([M+H⁺], C₂₂H₂₃N₄Orequires 359.1867).

Example 06-06 Preparation of3-((3-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-06)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355mmol) and 1-(azidomethyl)-4-fluorobenzene (0.107 g, 0.710 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 11 h. Purification wasdone by combiflash (SiO₂, 3%-5% methanol in dichloromethane) to yield3-((3-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.063 g, 49%). ¹H NMR (600 MHz, MeOD) δ 8.39 (1H, bs), 7.72 (1H, s),7.65 (1H, d, J=7.2 Hz), 7.46-7.42 (3H, m), 7.24 (1H, d, J=7.8 Hz),7.14-7.11 (2H, m), 5.63 (2H, s), 2.76 (2H, bs), 2.40-2.39 (2H, m), 1.68(3H, s); ¹³C NMR (150 MHz, MeOD) δ 205.2, 174.1, 147.3, 140.0, 131.6,131.5, 130.1, 129.7, 123.6, 122.5, 121.3, 120.7, 115.6, 115.5, 109.9,53.0, 32.7, 25.8, 5.7; LCMS m/z 363.4738 ([M+H⁺], C₂₁H₂₀FN₄O requires363.1616).

Example 06-07 Preparation of3-((3-(1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-07)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355mmol) and 1-(azidomethyl)-3-fluorobenzene (0.107 g, 0.710 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 11 h. Purification wasdone by combiflash (SiO₂, 3%-5% methanol in dichloromethane) to yield3-((3-(1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.115 g, 90%). ¹H NMR (600 MHz, MeOD) δ 8.42 (1H, bs), 7.74-7.73 (1H,m), 7.66 (1H, dd, J=1.2, 6.6 Hz), 7.47-7.40 (2H, m), 7.25 (1H, dd,J=2.4, 8.4 Hz), 7.19 (1H, d, J=7.8 Hz), 7.14-7.10 (2H, m), 5.67 (2H, s),2.78-2.77 (2H, m), 2.41-2.39 (2H, m), 1.69 (3H, s); ¹³C NMR (150 MHz,MeOD) δ 205.2, 174.1, 147.3, 140.0, 138.1, 131.5, 130.8, 130.7, 129.7,123.6, 122.5, 121.6, 120.7, 115.2, 115.1, 114.7, 114.6, 53.1, 32.7,25.8, 5.7; LCMS m/z 363.4598 ([M+H⁺], C₂₁H₂₀FN₄O requires 363.1616).

Example 06-08 Preparation of3-((3-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-08)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355mmol) and 1-(azidomethyl)-2-fluorobenzene (0.107 g, 0.710 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 11 h. Purification wasdone by combiflash (SiO₂, 3%-5% methanol in dichloromethane) to yield3-((3-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.115 g, 90%). ¹H NMR (600 MHz, DMSO-d⁶) δ 9.05 (1H, bs), 7.71 (1H, s),7.59 (1H, d, J=7.8 Hz), 7.44-7.38 (1H, m), 7.28-7.18 (3H, m), 5.70 (2H,s), 2.63 (2H, bs), 2.21-2.20 (2H, m), 1.56 (3H, s); ¹³C NMR (150 MHz,DMSO-d⁶) δ 202.5, 169.9, 146.8, 141.0, 131.9, 131.4, 130.2, 125.5,123.4, 123.3, 122.7, 122.5, 121.4, 119.9, 116.4, 116.2, 110.5, 47.7,33.5, 26.3, 8.0; LCMS m/z 363.3012 ([M+H⁺], C₂₁H₂₀FN₄O requires363.1616).

Example 06-09 Preparation of4-((4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide(06-09)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355mmol) and 4-(azidomethyl)benzamide (0.125 g, 0.710 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 20 h. Purification wasdone by washing the solid precipitate with dichloromethane to afford4-((4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide(0.120 g, 88%) as a white solid. ¹H NMR (600 MHz, DMSO-d⁶) δ 9.05 (1H,bs), 8.68 (1H, s), 7.97 (1H, s), 7.86 (1H, d, J=7.8 Hz), 7.71 (1H, s),7.58 (1H, d, J=7.2 Hz), 7.41-7.38 (2H, m), 7.18 (1H, d, J=7.2 Hz), 5.70(2H, s), 2.68 (2H, bs), 2.21-2.20 (2H, m), 1.56 (3H, s); ¹³C NMR (150MHz, DMSO-d⁶) δ 202.5, 169.8, 168.0, 147.0, 141.0, 139.6, 134.7, 132.0,128.6, 128.3, 122.6, 121.3, 119.9, 110.5, 53.3, 33.5, 26.3, 8.0; LCMSm/z 388.3432 ([M+H⁺], C₂₂H₂₂N₅O₂ requires 388.1768).

Example 06-10 Preparation of2-methyl-3-((3-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-10)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355mmol) and 1-(azidomethyl)-2-methylbenzene (0.104 g, 0.710 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 60 h. Purification wasdone by combiflash (SiO₂, 3%-7% methanol in dichloromethane) to yield2-methyl-3-((3-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.074 g, 58%). ¹H NMR (600 MHz, MeOD) δ 8.23 (1H, bs), 7.70 (1H, s),7.62 (1H, d, J=6.6 Hz), 7.41-7.40 (1H, m), 7.22-7.20 (4H, m), 5.64 (2H,s), 2.72 (2H, bs), 2.35-2.34 (5H, m), 1.66 (3H, s); LCMS m/z 359.4657([M+H⁺], C₂₂H₂₃N₄O requires 359.1867).

Example 06-11 Preparation of2-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-1,2,3-triazol-4-yl) phenyl)amino) cyclopent-2-enone (06-11)

Using the general procedure, a suspension of3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355mmol) and 3-(azidomethyl)pyridine (0.095 g, 0.710 mmol), sodiumascorbate, and copper (II) sulfate pentahydrate in a mixture of waterand tert-butyl alcohol were stirred at RT for 60 h. Purification wasdone by washing the solid precipitate with dichloromethane to afford2-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.067 g, 55%). ¹H NMR (600 MHz, MeOD) δ 8.63 (1H, s), 8.54-8.53 (1H,m), 8.45 (1H, s), 7.85 (1H, dd, J=1.2, 7.8 Hz), 7.72 (1H, s), 7.64 (1H,dd, J=0.6, 7.8 Hz), 7.47-7.42 (2H, m), 7.24-7.23 (1H, m), 5.73 (2H, s),2.74 (2H, bs), 2.38-2.37 (2H, m), 1.67 (3H, s); LCMS m/z 346.2856([M+H⁺], C₂₀H₂₀N₅O requires 346.1663).

Examples 06-12 and 06-13

Exam- ple TITLE COMPOUND 06-# NAME 123-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone 133-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclohex-2-enone

Example 06-12 Preparation of3-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone (06-12)

2-methylcyclohexane-1,3-dione (0.200 g, 1.58 mmol), 3-ethynylaniline(0.178 mL, 1.58 mmol), acetic acid (0.181 mL, 3.17 mmol), were added toa 0.5-2 mL Biotage® microwave vial. The biotage Intiator® microwavereactor was programmed to heat at 160° C. for 10 min. The reactionmixture was dissolved in methanol, concentrated in vacuo, purified bycombiflash (SiO₂, 2%-4% methanol in dichloromethane), to give3-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone (0.176 g, 49%) as awhite solid. ¹H NMR (600 MHz, MeOD) δ 7.34 (1H, t, J=7.8 Hz), 7.30 (1H,d, J=7.8 Hz), 7.25 (1H, bs), 7.17 (1H, d, J=8.4 Hz), 3.54 (1H, s), 2.47(2H, t, J=6 Hz), 2.34 (2H, t, J=6.6 Hz), 1.88-1.84 (2H, m), 1.77 (3H,s); ¹³C NMR (150 MHz, MeOD) δ 197.6, 162.0, 139.6, 129.0, 128.8, 128.4,125.8, 123.4, 107.1, 82.5, 78.2, 36.0, 27.3, 21.7, 7.6; LCMS m/z226.4831 ([M+H⁺], C₁₅H₁₆NO requires 226.1227).

Example 06-13 Preparation of3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclohex-2-enone(06-13)

To a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone(0.075 g, 0.332 mmol) and (azidomethyl)benzene (0.089 g, 0.666 mmol) ina mixture of water and tert-butyl alcohol (1:1, 1.5 mL) was added sodiumascorbate (0.035 mL, 0.036 mmol, 1 M solution in water), followed bycopper (II) sulfate pentahydrate (0.001 g, 0.004 mmol). Theheterogeneous mixture was stirred at RT for 10 h. The reaction mixturewas diluted with water (5 mL) and cooled in an ice bath. The ppt formedwas filtered and washed with water and dichloromethane. The filtrate wasextracted with dichloromethane, and the ppt was dissolved indichloromethane. The combined dichloromethane layers were dried (Na₂SO₄)and purified by combiflash (SiO₂, 2%-5% methanol in dichloromethane) togive3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclohex-2-enone(0.048 g, 40%) as a white solid. ¹H NMR (600 MHz, MeOD) δ 8.35 (1H, bs),7.63 (1H, d, J=7.8 Hz), 7.61 (1H, s), 7.40 (1H, t, J=7.8 Hz), 7.37-7.32(5H, m), 7.12 (1H, d, J=7.8 Hz), 5.62 (1H, d, J=10.8 Hz), 2.49 (2H, t,J=5.4 Hz), 2.31 (2H, t, J=6 Hz), 1.83-1.81 (2H, m), 1.79 (s, 3H); ¹³CNMR (150 MHz, MeOD) δ 197.4, 162.5, 147.2, 140.0, 135.5, 131.4, 129.5,128.8, 128.4, 127.9, 125.1, 122.6, 122.3, 121.4, 106.7, 53.8, 36.0,27.3, 21.8, 7.6; LCMS m/z 359.5227 ([M+H⁺], C₂₂H₂₃N₄O requires359.1867).

Examples 06-14 to 06-27

Example 06-# TITLE COMPOUND NAME R 143-((3-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂4-ClPh methylcyclopent-2-enone 153-((3-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)- CH₂ 4-2-methylcyclopent-2-enone OCH₃Ph 162-methyl-3-((3-(1-(naphthalen-1-ylmethyl)-1H-1,2,3-triazol-4- CH₂ 1-yl)phenyl)amino)cyclopent-2-enone Naphthyl 172-methyl-3-((3-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4- CH₂4-CF₃Ph yl)phenyl)amino)cyclopent-2-enone 182-methyl-3-((3-(1-(1-phenylethyl)-1H-1,2,3-triazol-4- CH₂yl)phenyl)amino)cyclopent-2-enone CH(CH₃)Ph 192-methyl-3-((3-(1-phenethyl-1H-1,2,3-triazol-4- CH₂ CH₂Phyl)phenyl)amino)cyclopent-2-enone 203-((3-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂2-ClPh methylcyclopent-2-enone 213-((3-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂3-ClPh methylcyclopent-2-enone 223-((3-(1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)- CH₂ 2-2-methylcyclopent-2-enone OCH₃Ph 233-((3-(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)- CH₂ 3-2-methylcyclopent-2-enone OCH₃Ph 242-methyl-3-((3-(1-(3-methylbenzyl)-1H-1,2,3-triazol-4- CH₂ 3-yl)phenyl)amino)cyclopent-2-enone CH₃Ph 253-((3-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2- CH₂4-BrPh methylcyclopent-2-enone 26(R)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-CH(COOH)Bn 1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid 27(S)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-CH(COOH)Bn 1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid

General synthesis procedure for3-((3-(1-substituted-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enones—06-14to 06-27. To a solution of substituted amine (1 Eq) in water (0.75mmol/mL) was added in sequence methanol (0.27 mmol/mL), NaHCO₃ (4 Eq), asolution of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl azide (1.5 Eq)in Et₂O (0.50 mmol/mL) and copper sulfate pentahydrate (0.1 Eq). Thereaction mixture was stirred at RT for 5 h. To the reaction mixture wasadded 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (1.1 Eq) andsodium ascorbate (1.5 Eq). The reaction mixture was stirred at RT forthe specified time. The reaction mixture was filtered, washed withdichloromethane (10 mL×3), filtrate was concentrated in vacuo andpurified as specified.

Example 06-14 Preparation of3-((3-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-14)

Using the general procedure (4-chlorophenyl)methanamine (0.085 g, 0.6mmol) was stirred for 60 h. Purification was done by combiflash (SiO₂,2%-7% methanol in dichloromethane) to yield3-((3-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.092 g, 41%). ¹H NMR (600 MHz, MeOD) δ 8.39 (1H, bs), 7.72 (1H, s),7.65 (1H, d, J=7.2 Hz), 7.46-7.38 (4H, m), 7.24 (1H, d, J=8.4 Hz), 5.64(2H, s), 2.77 (2H, bs), 2.40-2.39 (2H, m), 1.68 (3H, s); LCMS m/z379.2597 ([M+H⁺], C₂₁H₂₀ClN₄O requires 379.1321).

Example 06-15 Preparation of3-((3-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-15)

Using the general procedure (4-methoxyphenyl)methanamine (0.082 g, 0.6mmol) was stirred for 60 h. Purification was done by combiflash (SiO₂,3%-7% methanol in dichloromethane) to yield3-((3-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.117 g, 53%). ¹H NMR (600 MHz, MeOD) δ 8.32 (1H, bs), 7.71 (1H, s),7.64 (1H, d, J=7.2 Hz), 7.44 (1H, t, J=7.8 Hz), 7.34 (2H, d, J=8.4 Hz),7.24 (1H, d, J=7.2 Hz), 6.94 (2H, d, J=8.4 Hz), 5.56 (2H, s), 3.78 (3H,s), 2.76 (2H, bs), 2.39 (2H, bs), 1.68 (3H, s); LCMS m/z 375.3921([M+H⁺], C₂₂H₂₃N₄O₂ requires 375.1816).

Example 06-16 Preparation of2-methyl-3-((3-(1-(naphthalen-1-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-16)

Using the general procedure Naphthalen-1-ylmethanamine (0.094 g, 0.6mmol) was stirred for 40 h. Purification was done by combiflash (SiO₂,2%-7% methanol in dichloromethane) to yield2-methyl-3-((3-(1-(naphthalen-1-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.220 g, 94%). ¹H NMR (600 MHz, MeOD) δ 8.24 (1H, bs), 8.12 (1H, d,J=7.8 Hz), 7.89 (2H, d, J=6.6 Hz), 7.65 (1H, bs), 7.57-7.48 (5H, m),7.37 (1H, t, J=3.6 Hz), 7.17 (2H, d, J=7.2 Hz), 6.08 (2H, s), 2.67 (2H,bs), 2.31 (2H, bs), 1.65 (3H, s); LCMS m/z 395.2784 ([M+H⁺], C₂₅H₂₃N₄Orequires 395.1867).

Example 06-17 Preparation of2-methyl-3-((3-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-17)

Using the general procedure (4-(trifluoromethyl)phenyl)methanamine(0.105 g, 0.6 mmol) was stirred for 40 h. Purification was done bycombiflash (SiO₂, 3%-5% methanol in dichloromethane) to yield2-methyl-3-((3-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.201 g, 81%). ¹H NMR (600 MHz, MeOD) δ 8.43 (1H, bs), 7.72-7.63 (4H,m), 7.52 (2H, d, J=7.2 Hz), 7.42 (1H, t, J=7.2 Hz), 7.22 (1H, d, J=7.2Hz), 5.74 (2H, s), 2.72 (2H, bs), 2.36 (2H, bs), 1.66 (3H, s); LCMS m/z413.4756 ([M+H⁺], C₂₂H₂₀F₃N₄O requires 413.1584).

Example 06-18 Preparation of2-methyl-3-((3-(1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-18)

Using the general procedure 1-phenylethanamine (0.073 g, 0.6 mmol) wasstirred for 40 h. Purification was done by combiflash (SiO₂, 2%-7%methanol in dichloromethane) to yield2-methyl-3-((3-(1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.162 g, 75%). ¹H NMR (600 MHz, MeOD) δ 8.44 (1H, bs), 7.72 (1H, s),7.65 (1H, d, J=7.2 Hz), 7.43 (1H, t, J=7.8 Hz), 7.38-7.31 (5H, m), 7.22(1H, d, J=7.8 Hz), 5.94-5.93 (1H, m), 2.73 (2H, bs), 2.36 (2H, bs), 2.00(3H, d, J=6.6 Hz), 1.67 (3H, s); LCMS m/z 359.4603 ([M+H⁺], C₂₂H₂₃N₄Orequires 359.1867).

Example 06-19 Preparation of2-methyl-3-((3-(1-phenethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-19)

Using the general procedure 2-phenylethanamine (0.073 g, 0.6 mmol) wasstirred for 40 h. Purification was done by combiflash (SiO₂, 2%-7%methanol in dichloromethane) to yield2-methyl-3-((3-(1-phenethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.132 g, 61%). ¹H NMR (600 MHz, MeOD) δ 8.14 (1H, bs), 7.65 (1H, s),7.59 (1H, d, J=6 Hz), 7.45-7.44 (1H, m), 7.26-7.17 (6H, m), 4.70-4.69(2H, m), 3.28-3.27 (2H, m), 2.77 (2H, bs), 2.41 (2H, bs), 1.69 (3H, s);LCMS m/z 359.4236 ([M+H⁺], C₂₂H₂₃N₄O requires 359.1867).

Example 06-20 Preparation of3-((3-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-20)

Using the general procedure (2-chlorophenyl)methanamine (0.085 g, 0.6mmol) was stirred for 40 h. Purification was done by combiflash (SiO₂,2%-7% methanol in dichloromethane) to yield3-((3-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.116 g, 65%). ¹H NMR (600 MHz, MeOD) δ 8.35 (1H, bs), 7.73 (1H, s),7.66 (1H, d, J=7.2 Hz), 7.50-7.31 (5H, m), 7.25 (1H, d, J=7.8 Hz), 5.79(2H, s), 2.77 (2H, bs), 2.40 (2H, bs), 1.69 (3H, s); LCMS m/z 379.2943([M+H⁺], C₂₁H₂₀ClN₄O requires 379.1321).

Example 06-21 Preparation of3-((3-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-21)

Using the general procedure (3-chlorophenyl)methanamine (0.085 g, 0.6mmol) was stirred for 40 h. Purification was done by combiflash (SiO₂,2%-7% methanol in dichloromethane) to yield3-((3-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.130 g, 73%). ¹H NMR (600 MHz, MeOD) δ 8.41 (1H, bs), 7.73 (1H, s),7.66 (1H, bs), 7.45-7.26 (6H, m), 5.65 (2H, s), 2.77 (2H, bs), 2.40 (2H,bs), 1.68 (3H, s); LCMS m/z 379.2314 ([M+H⁺], C₂₁H₂₀ClN₄O requires379.1321).

Example 06-22 Preparation of3-((3-(1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-22)

Using the general procedure (2-methoxyphenyl)methanamine (0.085 g, 0.6mmol) was stirred for 40 h. Purification was done by combiflash (SiO₂,2%-7% methanol in dichloromethane) to yield3-((3-(1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.059 g, 33%). ¹H NMR (600 MHz, MeOD) δ 8.26 (1H, bs), 7.70 (1H, s),7.64 (1H, d, J=7.8 Hz), 7.43 (1H, dt, J=3, 7.8 Hz), 7.38-7.35 (1H, m),7.27-7.22 (2H, m), 7.04 (1H, dd, J=2.4, 8.1 Hz), 6.98-6.97 (1H, m), 5.62(2H, d, J=3 Hz), 3.88 (3H, t, J=1.8 Hz), 2.76 (2H, bs), 2.40-2.38 (2H,m), 1.68 (3H, s); LCMS m/z 375.4430 ([M+H⁺], C₂₂H₂₃N₄O₂ requires375.1816).

Example 06-23 Preparation of3-((3-(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-23)

Using the general procedure (3-methoxyphenyl)methanamine (0.082 g, 0.6mmol) was stirred for 40 h. Purification was done by combiflash (SiO₂,3%-5% methanol in dichloromethane) to yield3-((3-(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.152 g, 86%). ¹H NMR (600 MHz, MeOD) δ 8.36 (1H, bs), 7.72 (1H, s),7.65 (1H, d, J=7.2 Hz), 7.45-7.24 (3H, m), 6.93-6.91 (3H, m), 5.61 (2H,s), 3.78 (3H, s), 2.76 (2H, bs), 2.39 (2H, bs), 1.68 (3H, s); LCMS m/z375.4525 ([M+H⁺], C₂₂H₂₃N₄O₂ requires 375.1816).

Example 06-24 Preparation of2-methyl-3-((3-(1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(06-24)

Using the general procedure m-tolylmethanamine (0.073 g, 0.6 mmol) wasstirred for 40 h. Purification was done by combiflash (SiO₂, 2%-7%methanol in dichloromethane) to yield2-methyl-3-((3-(1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone(0.144 g, 85%). ¹H NMR (600 MHz, MeOD) δ 8.35 (1H, bs), 7.71 (1H, s),7.65 (1H, d, J=7.8 Hz), 7.44 (1H, t, J=8.4 Hz), 7.27-7.15 (5H, m), 5.61(2H, s), 2.76 (2H, bs), 2.39 (2H, bs), 2.34 (3H, s), 1.68 (3H, s); LCMSm/z 359.3305 ([M+H⁺], C₂₂H₂₃N₄O requires 359.1867).

Example 06-25 Preparation of3-((3-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-25)

Using the general procedure (4-bromophenyl)methanamine (0.112 g, 0.6mmol) was stirred for 40 h. Purification was done by combiflash (SiO₂,2%-7% methanol in dichloromethane) to yield3-((3-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.147 g, 74%). ¹H NMR (600 MHz, MeOD) δ 8.39 (1H, s), 7.72 (1H, t,J=1.8 Hz), 7.65 (1H, d, J=7.2 Hz), 7.56-7.55 (2H, m), 7.45 (1H, t, J=7.8Hz), 7.31 (2H, d, J=8.4 Hz), 7.25 (1H, dd, J=1.8, 7.8 Hz), 5.63 (2H, s),2.77-2.76 (2H, m), 2.41-2.39 (2H, m), 1.68 (3H, s); LCMS m/z 423.1297([M+H⁺], C₂₁H₂₀BrN₄O requires 423.0815).

Example 06-26 Preparation of(R)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoicacid (06-26)

Using the general procedure (R)-2-amino-3-phenylpropanoic acid (0.099 g,0.6 mmol) was stirred for 40 h. The reaction mixture acidified to pH 1with 1 M HCl, filtered and washed with dichloromethane to give(R)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoicacid (0.091 g, 48%). ¹H NMR (600 MHz, MeOD) δ 8.38 (1H, s), 7.67 (1H,s), 7.61 (1H, d, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz), 7.24-7.13 (6H, m),5.71 (1H, dd, J=4.2, 10.5 Hz), 3.69 (1H, dd, J=4.8, 14.4 Hz), 3.56 (1H,dd, J=10.8, 15.9 Hz), 2.77 (2H, bs), 2.41-2.40 (2H, m), 1.69 (3H, s);LCMS m/z 403.3882 ([M+H⁺], C₂₃H₂₃N₄O₃ requires 403.1765).

Example 06-27 Preparation of(S)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoicacid (06-27)

Using the general procedure (S)-2-amino-3-phenylpropanoic acid (0.099 g,0.6 mmol) was stirred for 40 h. The reaction mixture acidified to pH 1with 1 M HCl, filtered and washed with dichloromethane to give(S)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoicacid (0.040 g, 21%). ¹H NMR (600 MHz, MeOD) δ 8.38 (1H, d, J=3 Hz), 7.67(1H, d, J=1.8 Hz), 7.62-7.60 (1H, m), 7.46-7.42 (1H, m), 7.24-7.13 (6H,m), 5.72-5.70 (1H, m), 3.69 (1H, dd, J=4.2, 14.4 Hz), 3.56 (1H, dd,J=10.8, 14.4 Hz), 2.78-2.77 (2H, m), 2.41-2.40 (2H, m), 1.69 (3H, s);LCMS m/z 403.4457 ([M+H⁺], C₂₃H₂₃N₄O₃ requires 403.1765).

Example 06-28

Exam- ple TITLE COMPOUND 06-# NAME 283-((4-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone

Example 06-28 Preparation of3-((4-(4-benzyl-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-methylcyclopent-2-enone(06-28)

To a suspension of 4-ethynylaniline (0.117 g, 0.998 mmol) and(azidomethyl)benzene (0.266 g, 1.996 mmol) in a mixture of water andtert-butyl alcohol (1:1, 4 mL) was added sodium ascorbate (0.095 mL,0.099 mmol, 1 M solution in water), followed by copper (II) sulfatepentahydrate (0.002 g, 0.009 mmol). The heterogeneous mixture wasstirred at RT for 4 h. The reaction mixture was diluted with 5 mL waterand cooled in an ice bath. The precipitate formed was filtered andwashed with water and dichloromethane, extracted with dichloromethane,dried (Na₂SO₄) and purified by combiflash (SiO₂, 2%-4% methanol indichloromethane) to give 4-(1-benzyl-1H-1,2,3-triazol-4-yl)aniline(0.042 g, 17%) which was used for the next step without furtherpurification. LCMS m/z 251.3345 ([M+H⁺], C₂₀H₂₀N₅O requires 251.1292).

2-methylcyclopentane-1,3-dione (0.019 g, 0.167 mmol),4-(4-benzyl-1H-1,2,3-triazol-1-yl)aniline (0.042 g, 0.167 mmol), aceticacid (0.019 mL, 0.334 mmol), were added to a 0.5-2 mL Biotage® microwavevial. The biotage Intiator® microwave reactor was programmed to heat at160° C. for 30 min. The reaction mixture was purified by combiflash(SiO₂, 2%-5% methanol in dichloromethane), to give3-((4-(4-benzyl-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-methylcyclopent-2-enone(0.032 g, 55%). ¹H NMR (600 MHz, MeOD) δ 8.31 (1H, s), 7.83-7.82 (2H,m), 7.38-7.32 (6H, m), 5.64 (2H, s), 2.76 (2H, bs), 2.39 (2H, bs), 1.68(3H, s); LCMS m/z 345.3646 ([M+H⁺], C₂₁H₂₁N₄O requires 345.1710).

Biological Assays

Fluorescence Anisotropy Binding Assay

Expression and purification of the first bromodomain (BrD1) of humanBRD4 in poly-His tag form was performed using a procedure described inthe literature [See Zeng et al. Structure 16, 643-652 (2008) and Zhanget al., J Biol Chem 287, 28840-28851 (2012).] The protein was purifiedby using affinity chromatography on a nickel-IDA column (Invitrogen),followed by the removal of poly-His tag by thrombin cleavage.

Binding affinity of the newly synthesized compounds to the BRD4 BrD1 wasassessed in a fluorescence anisotropy assay using a fluoresceinisothiocyanate (FITC)-labeled MS417 as an assay probe (Zhang et al. 2008op.cit.). Competition binding was performed with a BrD protein (0.25 to1 μM) and the fluorescent probe (80 nM), and increasing concentration ofunlabeled competing ligand in a PBS buffer (pH 7.4) in total volume of80 μL. Measurements were obtained after 1 hour incubation of thefluorescent ligand and the protein at 25° C. with Safire 2 microplatereader (Tecan). In the assay, fluorescent ligand concentration was<2K_(d), and protein concentration was set at which 50-80% offluorescent ligand is bound. Dissociation constant of a competing ligandwas calculated with the correction to Cheng-Prussoff equation introducedby Nicolovska-Coleska and colleagues [Nikolovska-Coleska, Z. et al.,Anal Biochem 332, 261-273 (2004). Assuming one-site competitive bindingmodel, the equation used to calculate K_(i)'s from IC₅₀ values recoveredfrom fitting data using Prism:

${K_{i} = \frac{\left\lbrack I_{50} \right\rbrack}{\frac{\left\lbrack L_{50} \right\rbrack}{K_{d}} + \frac{\left\lbrack P_{0} \right\rbrack}{K_{d}} + 1}},$where [I₅₀] is the concentration of free inhibitor at 50% inhibition,[L₅₀], the concentration of free labeled ligand at 50% inhibition, and[P₀], concentration of free protein at 0% inhibition. Note that K_(d)for each protein-probe pair is the limit of resolvable K_(i) in acompetition assay. The binding results for examples above are listed inTable 1.

TABLE 1 Examples BRD4_1 BRD4_2 Examples BRD4_1 BRD4_2 Examples BRD4_1BRD4_2 01-# IC₅₀ IC₅₀ 02-# IC₅₀ IC₅₀ 03-# IC₅₀ IC₅₀ 01-1 ++ ++ 02-1 ++ +03-1 ++ ++ 01-2 ++ ++ 02-2 ++ ++ 03-2 + + 01-3 + ++ 02-3 + + 03-3 n.t.n.t. 01-4 ++ + 02-4 + + 03-4 n.t. n.t. 01-5 ++ ++ 02-5 + + 03-5 n.t.n.t. 01-6 + + 02-6 ++ + 03-6 ++ ++ 01-7 + + 02-7 ++ + 03-7 ++ ++ 01-8n.t. n.t. 02-8 ++ ++ 03-8 n.t. n.t. 01-9 ++ + 02-9 + + 03-9 ++ ++01-10 + + 02-10 ++ ++ 03-10 ++ ++ 01-11 ++ ++ 02-11 ++ + 03-11 ++ +01-12 ++ ++ 02-12 ++ ++ 03-12 n.t. n.t. 01-13 ++ ++ 02-13 ++ ++ 03-13n.t. n.t. 01-14 ++ ++ 02-14 ++ ++ 03-14 n.t. n.t. 01-15 n.t. n.t. 02-15++ ++ 03-15 n.t. n.t. 01-16 + + 03-16 ++ ++ 01-17 n.t. n.t. 03-17 n.t.n.t. 01-18 + + 03-18 ++ ++ 01-19 + + 03-19 ++ ++ 01-20 + + 03-20 + +01-21 ++ + 03-21 n.t. n.t. 01-22 ++ ++ 03-22 n.t. n.t. 01-23 + + 03-23++ ++ 01-24 ++ + 01-25 ++ + 01-26 ++ ++ 01-27 ++ ++ 01-28 + + 01-29 + +01-30 ++ ++ 01-31 ++ ++ 01-32 + + 01-33 + + 01-34 + + 01-35 ++ ++01-36 + + 01-37 + + 01-38 n.t. n.t. 01-39 n.t. n.t. 01-40 n.t. n.t.01-41 ++ ++ 01-42 +++ ++ 01-43 ++ ++ 01-44 ++ + 01-45 ++ ++ 01-46 ++ ++01-47 + + 01-48 ++ + 01-49 ++ + 01-50 + + 01-51 ++ + 01-52 ++ ++ 01-53+++ ++ 01-54 ++ ++ 01-55 ++ ++ 01-56 ++ + 01-57 ++ ++ 01-58 ++ ++ 01-59++ + 01-60 ++ ++ 01-61 + + 01-62 +++ ++ 01-63 ++ ++ 01-64 +++ ++Examples BRD4_1 BRD4_2 Examples BRD4_1 BRD4_2 Examples BRD4_1 BRD4_204-# IC₅₀ IC₅₀ 05-# IC₅₀ IC₅₀ 06-# IC₅₀ IC₅₀ 04-1 ++ ++ 05-1 n.t. n.t.06-1 ++ + 04-2 ++ ++ 05-2 n.t. n.t. 06-2 ++ ++ 04-3 ++ + 05-3 n.t. n.t.06-3 n.t. n.t. 04-4 ++ ++ 05-4 n.t. n.t. 06-4 +++ ++ 04-5 ++ ++ 05-5n.t. n.t. 06-5 n.t. n.t. 04-6 ++ + 05-6 n.t. n.t. 06-6 n.t. n.t. 04-7++ + 05-7 n.t. n.t. 06-7 n.t. n.t. 04-8 ++ ++ 05-8 n.t. n.t. 06-8 +++ ++04-9 n.t. n.t. 05-9 n.t. n.t. 06-9 n.t. n.t. 04-10 n.t. n.t. 05-10 n.t.n.t. 06-10 +++ ++ 04-11 n.t. n.t. 05-11 n.t. n.t. 06-11 n.t. n.t. 04-12n.t. n.t. 05-12 ++ ++ 06-12 n.t. n.t. 04-13 ++ ++ 05-13 n.t. n.t. 06-13n.t. n.t. 04-14 +++ ++ 05-14 +++ ++ 06-14 n.t. n.t. 04-15 +++ ++ 05-15+++ ++ 06-15 +++ ++ 04-16 ++ ++ 05-16 n.t. n.t. 06-16 n.t. n.t. 04-17+++ ++ 05-17 ++ ++ 06-17 n.t. n.t. 04-18 +++ ++ 05-18 +++ ++ 06-18 n.t.n.t. 04-19 +++ ++ 05-19 n.t. n.t. 06-19 n.t. n.t. 04-20 +++ ++ 05-20n.t. n.t. 06-20 n.t. n.t. 04-21 +++ ++ 05-21 n.t. n.t. 06-21 n.t. n.t.04-22 ++ ++ 05-22 n.t. n.t. 06-22 n.t. n.t. 04-23 n.t. n.t. 05-23 n.t.n.t. 06-23 n.t. n.t. 04-24 n.t. n.t. 05-24 n.t. n.t. 06-24 n.t. n.t.04-25 n.t. n.t. 05-25 n.t. n.t. 06-25 n.t. n.t. 04-26 + + 05-26 n.t.n.t. 06-26 n.t. n.t. 04-27 n.t. n.t. 05-27 n.t. n.t. 06-27 n.t. n.t.04-28 n.t. n.t. 05-28 n.t. n.t. 06-28 +++ ++ 04-29 n.t. n.t. 05-29 n.t.n.t. 04-30 + + 05-30 n.t. n.t. 04-31 n.t. n.t. 05-31 n.t. n.t. 04-32 + +05-32 + + 04-33 n.t. n.t. 05-33 + + 04-34 n.t. n.t. 05-34 + + 04-35 n.t.n.t. 05-35 + + 04-36 + + 05-36 + + 04-37 n.t. n.t. 05-37 +++ + 04-38n.t. n.t. 05-38 +++ +++ 04-39 n.t. n.t. 05-39 +++ ++ 04-40 + + 05-40 ++++++ 04-41 n.t. n.t. 05-41 +++ ++ 04-42 n.t. n.t. 05-42 +++ ++ 04-43 + +05-43 + + 04-44 ++ + 05-44 +++ ++ 04-45 + + 05-45 +++ ++ 04-46 ++ +05-46 +++ ++ 04-47 + + 05-47 +++ ++ 04-48 ++ ++ 05-48 +++ ++ 04-49 ++ +05-49 +++ ++ 04-50 + + 05-50 ++ + 04-51 + + 05-51 ++ + 04-52 + + 05-52+++ ++ 04-53 ++ ++ 05-53 ++ ++ 04-54 ++ ++ 05-54 +++ +++ 04-55 ++ ++05-55 +++ ++ 04-56 ++ ++ 05-56 +++ +++ 04-57 ++ ++ 05-57 +++ +++ 04-58++ ++ 05-58 +++ +++ 04-59 ++ ++ 05-59 +++ +++ 04-60 ++ ++ 05-60 +++ +++04-61 ++ ++ 05-61 +++ +++ 04-62 ++ ++ 05-62 +++ ++ 04-63 n.t. n.t. 05-63+++ ++ 04-64 n.t. n.t. 05-64 +++ ++ 04-65 ++ ++ 05-65 +++ ++ 04-66 ++ ++05-66 +++ +++ 04-67 +++ + 05-67 +++ +++ 04-68 ++ ++ 05-68 +++ ++ 04-69+++ + 05-69 +++ ++ 04-70 ++ ++ 05-70 +++ + 04-71 ++ ++ 05-71 +++ ++04-72 +++ ++ 05-72 +++ +++ 04-73 ++ ++ 05-73 ++ ++ 04-74 ++ ++ 05-74 ++++++ 04-75 n.t. n.t. 05-75 +++ ++ 04-76 n.t. n.t. 05-76 ++ + 04-77 ++ +05-77 ++ ++ 04-78 ++ ++ 05-78 +++ ++ 04-79 ++ ++ 05-79 ++ + 04-80 ++ ++05-80 +++ ++ 04-81 ++ ++ 05-81 +++ ++ 04-82 ++ ++ 05-82 +++ + 04-83 ++++ 05-83 ++ + 04-84 ++ ++ 05-84 ++ + 04-85 ++ ++ 05-85 +++ + 04-86 ++ ++04-87 n.t. n.t. 04-88 n.t. n.t. 04-89 +++ ++ 04-90 n.t. n.t. 04-91 ++ ++04-92 ++ + 04-93 ++ ++ 04-94 n.t. n.t. 04-95 + + 04-96 ++ + 04-97 ++ +04-98 + + 04-99 ++ ++ 04-100 n.t. n.t. 04-101 n.t. n.t. 04-102 n.t. n.t.04-103 n.t. n.t. 04-104 +++ ++ 04-105 +++ ++ 04-106 +++ ++ Note: n.t. =not tested; (+) = >10 uM; (++) = 1-10 uM; (+++) = <1 uM

LPS-Induced IL-6 Secretion in Murine Macrophage Raw264.7 Cells RAW264.7cells were cultivated in Dulbecco's modified Eagle medium (DMEM)(Hyclone, Logan, Utah) supplemented with 10% FBS (fetal bovine serum)(Hyclone, Logan, Utah) at 37° C. in a humidified atmosphere of 5% CO₂.Cells in 96-well plates (0.1 ml, 3×10⁵ cells/ml) were treated with thetest compounds. After 30 min, all supernatants were removed and cellswere treated with LPS (lipopolysaccharide) (1 μg/ml) (Sigma-AldrichChemical Co., St. Louis, Mo.) and compounds. After 24 hours, thesupernatant was collected and mouse IL-6 protein level was measuredusing ELISA (enzyme-linked immunosorbent assay) (Thermo Scientific,Pittsburgh, Pa.). The compounds dissolved in DMSO were diluted withculture medium to concentrations from 0.28 to 50,000 nM. The finalconcentration of DMSO was adjusted to 0.05% (v/v). The assay wasmeasured by an absorption reading at 570 nm using EnVison 2104Multilabel Reader (PerkinElmer, Inc., Waltham, Mass.). Each experimentwas performed at least in triplicate, and plotted using Prim, and anIC₅₀ value was calculated. Examples 04-19 and 04-20 were tested in thisassay and found to have IC₅₀ values in the range of 0.2-1 μM.

LPS-Induced Transcriptional Activation of Cytokines in Murine MacrophageCells RAW264.7 cells were cultivated with or without a treatment of thecompounds as described above. Total RNA was isolated the cells usingTRIzol reagent (Gibco, Grand Island, N.Y.) for homogenization. Theconcentration and integrity of RNA were determined by measuringabsorbance at a 260 nm/280 nm ratio. Quantitative PCR was performed todetermine the mRNA transcript levels of cytokines IL-6, IL-1β and TNFαwith specific primers for these target genes. Each experiment wasperformed at least in triplicate, and plotted using Prim, and an IC₅₀value was calculated. Examples 01-36, 04-15, 04-17, 04-19, 04-20, 04-89,04-91, 04-98, 05-15, and 06-4 were tested in this assay and found tohave IC₅₀ values in the range of 0.1-5 μM in inhibition oftranscriptional activation of the cytokines IL-6, IL-1β and TNFα.

LPS-Stimulated Nitric Oxide (NO) Release in Murine Macrophage RAW264.7Cells

RAW264.7 cells was cultivated in DMEM supplemented with 10% FBS at 37°C. in a humidified atmosphere of 5% CO₂. Cells in 96-well plates (0.1ml, 3×10⁵ cells/ml) were treated with the test compounds. After 30 min,all supernatants were removed and cells were treated with LPS (1 μg/ml)and the test compounds. After 24 hours, the level of nitrite wasmeasured using Griess reaction G2930 (Promega Corp., Madison, Wis.) [seeBredt and Snyder, Ann Rev Biochem 63, 175-195 (1994)]. The testcompounds dissolved in DMSO were diluted with culture medium toconcentrations from 0.28 to 50,000 nM. The final concentration of DMSOwas adjusted to 0.05% (v/v). The nitrite production was measured byspectrophotometry at 520 nm using EnVison 2104 Multilabel Reader(PerkinElmer, Inc., Waltham, Mass.). Each experiment was performed atleast in triplicate and plotted using Prism. Examples 01-36, 04-15,04-17, 04-19, 04-20, 04-89, 04-91, 04-98, 05-15, and 06-4 were tested inthis assay and found to have IC₅₀ values in the range of 0.1-5 μM ininhibition of LPS-induced NO release in RAW264.7 cells.

ELISA Assay Assessing IL-8 Expression in BLBCs

Compounds of the Examples listed in Table 1 (“test compounds”) wereevaluated for their activity to inhibit expression of IL-8 in humanbasal-like breast cancer cells (BLBCs). The human BLBCs were cultivatedin DMEM (Hyclone, Logan, Utah) supplemented with 10% FBS (Hyclone,Logan, Utah) at 37° C. in a humidified atmosphere of 5% CO₂. Upon 60-80%confluency of the culturing dish, the cells were trypsinized,centrifuged at 1000 rpm for 5 min, and resuspended with fresh culturingmedium for seeding of cells in a 96-well plate (0.1 ml, 3×10⁵ cells/ml)and incubated at the above-mentioned culturing conditions overnight. Thefollowing day upon cells adhesion to the plate bottom, all supernatantswere carefully discarded followed by adding test compounds diluted inculturing medium. The test compounds dissolved in DMSO (Sigma-AldrichChemical Co., St. Louis, Mo.) were diluted with culturing medium in a2-fold serial dilution from 1000 nM to 125 nM. The final concentrationof DMSO was adjusted to 0.05% (v/v). At the end of 24-hour incubation,all supernatants were carefully removed and stored at −80° C. if thesubsequent steps would not be performed immediately. The Human IL-8ELISA Ready-Set-Go! (2^(nd) generation) is used (Catalog No. 88-8086)against the prepared samples. The samples along with the Standard HumanIL-8 Recombinant Protein (prepared in duplicates in a 2-fold serialdilution from 250 pg/ml to 2 pg/ml) were incubated overnight for maximalsensitivity. The assay was measured by an absorption reading at 450 nmusing EnVision 2104 Multilabel Reader (PerkinElmer, Inc., Waltham,Mass.). Each experiment was performed at least in duplicate and plottedusing Prism. The curve fitting equation used was “log(inhibitor) vs.response-variable slope (four parameters)”. Examples 05-57, 05-68, and05-70 were tested in this assay in a panel of human BLBC cellsconsisting of MDA-MB-435S, MDA-MB-231, BT-549, MDA-MB-157, HS578T, andSUM1315, and found to have IC₅₀ values in the range of 0.1-1 μM.

Human, Rat, and Mouse Microsome Stability Assay

Microsome stability assays were performed on Compounds of the Exampleslisted in Table 1 (“test compounds”). Human, rat, and mouse livermicrosomal incubations were carried out at 37° C. with a finalincubation volume of 135 μL. Human liver microsomes (mixed gender,Catalog No, H12610) were obtained from XenoTech. Rat liver microsomes(male Sprague-Dawley, Catalog No. 452501) were obtained from BD Gentest.Mouse liver microsomes (male CD1, Catalog No. 452701) were obtained fromBD Gentest. Incubations were conducted using a test compound (initiallydissolved in DMSO at 5 μM concentration) concentration of 0.5 μM and0.25 mg/mL microsomal protein in 50 mM phosphate buffer at pH 7.4. Timezero samples were prepared by transferring 13.5 μL ofcompound-microsomal mix to the quench plates containing 45 μL of quenchsolution made of 10 nM Buspirone (Sigma) or 50 nM Carbutamide (PrincetonBio) as internal standard in 1:1 methanol:acetonitrile. An aliquot of1.5 μL Nicotinamide adenine dinucleotide phosphate reduced tetrasodiumsalt (NADPH) was also added to the time zero plates. The reaction wasthen initiated by the addition of 13.5 μL NADPH to thecompound-microsomal mix. At each of the remaining time points (5, 10,15, 20, 30, 45 and 60 min) 15 μL of incubation mixture was added to 45μL of quench solution. Samples were centrifuged for 15-30 minutes at3800 rpm. Samples were then pooled for 6 per group. An aliquot of 60 μLof supernatant was transferred to 96-well plate, and a 5 μL aliquot wasinjected and analyzed by LC-MS (Applied Biosystems API 5500 QTrap). Theintrinsic clearance of a compound was calculated by converting the peakarea ratios (analyte peak area/IS peak area) to % parent remaining usingthe area ratio at time 0 as 100%. The slope (k) was determined from theplot of the % parent remaining versus incubation time, from which thehalf life (t½; minutes), intrinsic clearance (CLint; μL/min/mg proteinfor liver microsomes and μL/min/million cells for hepatocytes) andscaled intrinsic clearance (scaled CLint; L/h/kg) were then derived.Examples 01-41, 01-47, 05-57, 05-66, 05-68, and 05-70 were tested inthis assay and found to have the intrinsic clearance CLint values in therange of 25-250 L/min/mg protein.

T-Cell-Transfer Colitis Study and Histopathology

Compound of Example 04-19 inhibits the development of colitis in mice asexamined in the established T-cell-transfer colitis model [See (Totsuka,T. et al. J Immunol 178, 4737-4748 (2007) and Powrie, F. et al.International immunology 5, 1461-1471 (1993).] Briefly, purifiedCD4⁺CD45RB^(hi) T cells from C57BL/6 mice were injectedintra-peritoneally into Rag1^(−/−) recipients (5×10⁵ cells per mouse in200 μl sterile PBS per injection). Mice were weighed every weekthroughout the course of experiments. FIG. 1 presents the results ingraph form. It can be seen that compound 04-19 significantly (P<0.05)inhibits the loss of body weight. After 5-7 weeks, mice were killed andcolon tissues were excised. Tissues were fixed in 10% buffered formalinand paraffin embedded. The sections (5 m) of tissue samples stained withhematoxylin and eosin. All the slides were read and scored by anexperienced pathologist without previous knowledge of the type oftreatment. The degree of inflammation in the epithelium, submucosa andmuscularis propria was scored separately. It can be seen from FIG. 2that the gross morphology of the intestines is preserved in the treatedmice and lost in the disease group.

What is claimed:
 1. A method for treating a disease or disorder arisingfrom inappropriate activity of proteins containing an acetyl-lysineresidue, said method comprising administering to a patient in needthereof a therapeutically effective amount of a compound of formula I

wherein: U is (CH₂)_(n), where n=1, 2 or 3; R¹ is selected from thegroup consisting of: (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)alkyl, andnitrile; Cy is a carbocycle or heterocycle; R¹¹ and R¹² areindependently selected from the group consisting of: H, (C₁-C₁₀)alkyl,(C₁-C₁₀)perfluoroalkyl, halogen, nitrile, hydroxy, (C₁-C₁₀)alkoxy,perfluoro(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, amino, (C₁-C₁₀)alkylamino,(C₁-C₁₀)acylamino, aryl, heteroaryl, aminocarbonyl, carboxyl, and(C₁-C₁₀)alkoxycarbonyl; or taken together, R¹¹ and R¹² may form a 5, 6,or 7-membered carbocycle or heterocycle wherein said carbocycle orheterocycle may be optionally substituted with R²; R² is selected fromthe group consisting of: halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, carboxy, amino,(C₁-C₄)alkylamino and di(C₁-C₄)alkylamino; Y is selected from,

L and L′ are independently a bond or (CR³R⁴)_(m) where R³ and R⁴ areindependently selected from the group consisting of H and (C₁-C₄)alkyl,and m is 1 or 2; R¹⁰ is chosen from alkyl, carbocycle and heterocycle,wherein said alkyl, carbocycle or heterocycle is optionally substitutedwith R⁷ and/or R⁸; R²⁰ is —C(═O)OR²¹; R²¹ is chosen from H and(C₁-C₄)alkyl; R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen, hydroxy, (C₁-C₁₀) hydrocarbyl,halo(C₁-C₁₀)hydrocarbyl, and (C₁-C₁₀)alkoxy; R⁷ and R⁸ are independentlyselected from the group consisting of: hydroxy, halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylcarbonyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, cyano, oxo, (C₁-C₄)alkylsulfonyl, amino,(C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, (C₁-C₄)acylamino, aminocarbonyl,carboxyl, and (C₁-C₄)alkoxycarbonyl, where each said alkyl, aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, may be further optionallysubstituted with hydroxy, oxo, carboxy, carboxy(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl, amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, amido, (C₁-C₄)alkylamido, di (C₁-C₄)alkylamido,halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, aryl, heteroaryl,heterocycloalkyl, or cycloalkyl; or, taken together, R⁵ and R⁶, or R⁷and R⁸ may form a 5, 6, or 7-membered carbocycle or heterocycle, whereinsaid carbocycle or heterocycle is optionally substituted with R⁹; R⁹ isselected from the group consisting of: halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, amino,(C₁-C₄)alkylamino and di(C₁-C₄)alkylamino.
 2. The method of claim 1,wherein the disease or disorder is chronic inflammation.
 3. The methodof claim 2 wherein the disease or disorder is inflammatory colitis. 4.The method of claim 1, wherein the treatment of a disease or a disorderfurther comprises administering an additional therapeutic agent.
 5. Amethod for inhibiting bromodomain in a cell, comprising contacting thecell with an inhibitory amount of a compound of formula I

wherein: U is (CH₂)_(n), where n=1, 2 or 3; R¹ is selected from thegroup consisting of: (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)alkyl, andnitrile; Cy is a carbocycle or heterocycle; R¹¹ and R¹² areindependently selected from the group consisting of: H, (C₁-C₁₀)alkyl,(C₁-C₁₀)perfluoroalkyl, halogen, nitrile, hydroxy, (C₁-C₁₀)alkoxy,perfluoro(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, amino, (C₁-C₁₀)alkylamino,(C₁-C₁₀)acylamino, aryl, heteroaryl, aminocarbonyl, carboxyl, and(C₁-C₁₀)alkoxycarbonyl; or taken together, R¹¹ and R¹² may form a 5, 6,or 7-membered carbocycle or heterocycle wherein said carbocycle orheterocycle may be optionally substituted with R²; R² is selected fromthe group consisting of: halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, carboxy, amino,(C₁-C₄)alkylamino and di(C₁-C₄)alkylamino; Y is selected from,

L and L′ are independently a bond or (CR³R⁴)_(m) where R³ and R⁴ areindependently selected from the group consisting of H and (C₁-C₄)alkyl,and m is 1 or 2; R¹⁰ is chosen from alkyl, carbocycle and heterocycle,wherein said alkyl, carbocycle or heterocycle is optionally substitutedwith R⁷ and/or R⁸; R²⁰ is —C(═O)OR²¹; R²¹ is chosen from H and(C₁-C₄)alkyl; R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen, hydroxy, (C₁-C₁₀) hydrocarbyl,halo(C₁-C₁₀)hydrocarbyl, and (C₁-C₁₀)alkoxy; R⁷ and R⁸ are independentlyselected from the group consisting of: hydroxy, halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylcarbonyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, cyano, oxo, (C₁-C₄)alkylsulfonyl, amino,(C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, (C₁-C₄)acylamino, aminocarbonyl,carboxyl, and (C₁-C₄)alkoxycarbonyl, where each said alkyl, aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, may be further optionallysubstituted with hydroxy, oxo, carboxy, carboxy(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl, amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, amido, (C₁-C₄)alkylamido, di (C₁-C₄)alkylamido,halogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, aryl, heteroaryl,heterocycloalkyl, or cycloalkyl; or, taken together, R⁵ and R⁶, or R⁷and R⁸ may form a 5, 6, or 7-membered carbocycle or heterocycle, whereinsaid carbocycle or heterocycle is optionally substituted with R⁹; R⁹ isselected from the group consisting of: halogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, amino,(C₁-C₄)alkylamino and di(C₁-C₄)alkylamino.
 6. The method of claim 1,wherein the disease or disorder is autoimmune disease.
 7. The method ofclaim 1, wherein the disease or disorder is cancer.
 8. The method ofclaim 7, wherein the cancer is selected from breast cancer, triplenegative breast cancer, prostate cancer, acute leukemia, chronicleukemia, chronic lymphocytic leukemia, colon cancer, colorectal cancer,multiple myeloma, glioblastoma, lung cancer, and liver cancer.
 9. Themethod of claim 2, wherein the disease or disorder is selected frommultiple sclerosis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, type I diabetes, rheumatoid arthritis, AIDS, andasthma.
 10. The method of claim 3, wherein: R¹ is selected from thegroup consisting of: (C₁-C₁₀)alkyl, (C₁-C₁₀)alkyl substituted with oneor more fluorine, and nitrile; Cy is selected from the group consistingof: phenyl, naphthalene, pyridine, quinoline, isoquinoline, indole, orbenzimidazole; R¹¹ and R¹² are independently selected from the groupconsisting of: H, (C₁-C₁₀)alkyl, (C₁-C₁₀)perfluoroalkyl, halogen,(C₁-C₁₀)alkoxy, amino, hydroxy, (C₁-C₁₀)alkylamino, (C₁-C₁₀)acylamino,aryl, heteroaryl, aminocarbonyl, carboxyl, and (C₁-C₁₀)alkoxycarbonyl;or taken together, R¹¹ and R¹² may form a 5, 6, or 7-membered carbocycleor heterocycle wherein said carbocycle or heterocycle may be optionallysubstituted with R²; and Y is selected from:


11. The method of claim 10, wherein the disease or disorder is chronicinflammation.
 12. The method of claim 11, wherein the disease ordisorder is inflammatory colitis.
 13. The method of claim 10, whereinthe treatment of a disease or a disorder further comprises administeringan additional therapeutic agent.
 14. The method of claim 5, wherein: R¹is selected from the group consisting of: (C₁-C₁₀)alkyl, (C₁-C₁₀)alkylsubstituted with one or more fluorine, and nitrile; Cy is selected fromthe group consisting of: phenyl, naphthalene, pyridine, quinoline,isoquinoline, indole, or benzimidazole; R¹¹ and R¹² are independentlyselected from the group consisting of: H, (C₁-C₁₀)alkyl,(C₁-C₁₀)perfluoroalkyl, halogen, (C₁-C₁₀)alkoxy, amino, hydroxy,(C₁-C₁₀)alkylamino, (C₁-C₁₀)acylamino, aryl, heteroaryl, aminocarbonyl,carboxyl, and (C₁-C₁₀)alkoxycarbonyl; or taken together, R¹¹ and R¹² mayform a 5, 6, or 7-membered carbocycle or heterocycle wherein saidcarbocycle or heterocycle may be optionally substituted with R²; and Yis selected from:


15. The method of claim 10, wherein the disease or disorder isautoimmune disease.
 16. The method of claim 10, wherein the disease ordisorder is cancer.
 17. The method of claim 16, wherein the cancer isselected from breast cancer, triple negative breast cancer, prostatecancer, acute leukemia, chronic leukemia, chronic lymphocytic leukemia,colon cancer, colorectal cancer, multiple myeloma, glioblastoma, lungcancer, and liver cancer.
 18. The method of claim 11, wherein thedisease or disorder is selected from multiple sclerosis, inflammatorybowel disease, Crohn's disease, ulcerative colitis, type I diabetes,rheumatoid arthritis, AIDS, and asthma.